Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

AbstractReduced cardiac sodium (Na+) channel current (INa) resulting from the loss-of-function of Na+ channel is a major cause of lethal arrhythmias in Brugada syndrome (BrS). Inspired by previous experimental studies which showed that in heart diseases INa was reduced along with expression changes in Na+ channel within myocytes, we hypothesized that the local decrease in INa caused by the alteration in Na+ channel expression in myocytes leads to the occurrence of phase-2 reentry, the major triggering mechanism of lethal arrhythmias in BrS. We constructed in silico human ventricular myocardial strand and ring models, and examined whether the Na+ channel expression changes in each myocyte cause the phase-2 reentry in BrS. Reducing Na+ channel expression in the lateral membrane of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, the selective reduction in Na+ channels on the lateral membrane of each myocyte together with spatial tissue heterogeneity of Na+ channel expression caused the phase-2 reentry and phase-2 reentry-mediated reentrant arrhythmias. Our data suggest that the BrS phenotype is strongly influenced by expression abnormalities as well as genetic abnormalities of Na+ channels.

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Specific decreasing of Na+ channel expression on the lateral membrane of cardiomyocytes causes fatal arrhythmias in Brugada syndrome

10.1101/805986 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kunichika Tsumoto ◽

Takashi Ashihara ◽

Narumi Naito ◽

Takao Shimamoto ◽

Akira Amano ◽

...

Keyword(s):

Brugada Syndrome ◽

Ventricular Myocytes ◽

Tissue Level ◽

Poor Correlation ◽

Na Channel ◽

Loss Of Function ◽

Channel Distribution ◽

Lateral Membrane ◽

Channel Expression ◽

Lethal Arrhythmia

ABSTRACTOne phenotypic feature of Brugada syndrome (BrS) is slowed conduction due to the reduction (loss-of-function) of Na+ channels. In contrast, recent clinical observations in BrS patients highlighted the poor correlation between the phenotype (typical ECG change or lethal arrhythmia) and the genotype (SCN5A mutation). Inspired by our previous theoretical study which showed that reduced Na+ channels in the lateral membrane (LM) of ventricular myocytes caused the slowing of conduction under myocardial ischemia, we hypothesized that a loss-of-function of Na+ channels caused by the decreases in Na+ channel expression within myocytes leads to phase-2 reentry (P2R), the major triggering mechanism of lethal arrhythmias in BrS. We constructed an in silico human ventricular myocardial strand and ring models, and investigated the relationship between the subcellular Na+ channel distribution and P2R. Reducing Na+ channel expression in the LM of each myocyte caused not only the notch-and-dome but also loss-of-dome type action potentials and slowed conduction, both of which are typically observed in BrS patients. Furthermore, we showed that both the reduction in Na+ channels on the LM of each myocyte and tissue-level heterogeneity of Na+ channel expression were essential for P2R as well as P2R-mediated reentrant excitation. Our data suggest that the alteration in subcellular Na+ channel distribution together with a tissue-level heterogeneity of Na+ channels can cause arrhythmogenesis in BrS.

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Sodium channel current loss of function in induced pluripotent stem cell-derived cardiomyocytes from a Brugada syndrome patient

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2017.10.002 ◽

2018 ◽

Vol 114 ◽

pp. 10-19 ◽

Cited By ~ 18

Author(s):

Elisabet Selga ◽

Franziska Sendfeld ◽

Rebecca Martinez-Moreno ◽

Claire N. Medine ◽

Olga Tura-Ceide ◽

...

Keyword(s):

Stem Cell ◽

Sodium Channel ◽

Brugada Syndrome ◽

Pluripotent Stem Cell ◽

Induced Pluripotent Stem Cell ◽

Syndrome Patient ◽

Loss Of Function ◽

Current Loss ◽

Channel Current ◽

Induced Pluripotent

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Potential Role of Inflammation in Associations between Particulate Matter and Heart Failure

Current Pharmaceutical Design ◽

10.2174/1381612824666180110150550 ◽

2018 ◽

Vol 24 (3) ◽

pp. 341-358 ◽

Cited By ~ 7

Author(s):

Xiaotong Ji ◽

Yingying Zhang ◽

Guangke Li ◽

Nan Sang

Keyword(s):

Heart Failure ◽

Particulate Matter ◽

Inflammatory Response ◽

Heart Diseases ◽

Experimental Studies ◽

Epidemiological Studies ◽

Inflammatory Mechanism ◽

High Concentrations ◽

Future Work ◽

The Relationship

Recently, numerous studies have found that particulate matter (PM) exposure is correlated with increased hospitalization and mortality from heart failure (HF). In addition to problems with circulation, HF patients often display high expression of cytokines in the failing heart. Thus, as a recurring heart problem, HF is thought to be a disorder characterized in part by the inflammatory response. In this review, we intend to discuss the relationship between PM exposure and HF that is based on inflammatory mechanism and to provide a comprehensive, updated evaluation of the related studies. Epidemiological studies on PM-induced heart diseases are focused on high concentrations of PM, high pollutant load exposure in winter, or susceptible groups with heart diseases, etc. Furthermore, it appears that the relationship between fine or ultrafine PM and HF is stronger than that between HF and coarse PM. However, fewer studies paid attention to PM components. As for experimental studies, it is worth noting that coarse PM may indirectly promote the inflammatory response in the heart through systematic circulation of cytokines produced primarily in the lungs, while ultrafine PM and its components can enter circulation and further induce inflammation directly in the heart. In terms of PM exposure and enhanced inflammation during the pathogenesis of HF, this article reviews the following mechanisms: hemodynamics, oxidative stress, Toll-like receptors (TLRs) and epigenetic regulation. However, many problems are still unsolved, and future work will be needed to clarify the complex biologic mechanisms and to identify the specific components of PM responsible for adverse effects on heart health.

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A Melanocortin-4 Receptor Agonist Induces Skin and Hair Pigmentation in Patients with Monogenic Mutations in the Leptin-Melanocortin Pathway

Skin Pharmacology and Physiology ◽

10.1159/000516282 ◽

2021 ◽

pp. 1-10

Author(s):

Varvara Kanti ◽

Lia Puder ◽

Irina Jahnke ◽

Philipp Maximilian Krabusch ◽

Jan Kottner ◽

...

Keyword(s):

Leptin Receptor ◽

Skin Pigmentation ◽

Gene Mutations ◽

Continuous Treatment ◽

Whole Body ◽

Hair Color ◽

Phase 2 ◽

Loss Of Function ◽

The Impact ◽

Over Time

Background and Objectives: Gene mutations within the leptin-melanocortin signaling pathway lead to severe early-onset obesity. Recently, a phase 2 trial evaluated new pharmacological treatment options with the MC4R agonist setmelanotide in patients with mutations in the genes encoding proopiomelanocortin (POMC) and leptin receptor (LEPR). During treatment with setmelanotide, changes in skin pigmentation were observed, probably due to off-target effects on the closely related melanocortin 1 receptor (MC1R). Here, we describe in detail the findings of dermatological examinations and measurements of skin pigmentation during this treatment over time and discuss the impact of these changes on patient safety. Methods: In an investigator-initiated, phase 2, open-label pilot study, 2 patients with loss-of-function POMC gene mutations and 3 patients with loss-of-function variants in LEPR were treated with the MC4R agonist setmelanotide. Dermatological examination, dermoscopy, whole body photographic documentation, and spectrophotometric measurements were performed at screening visit and approximately every 3 months during the course of the study. Results: We report the results of a maximum treatment duration of 46 months. Skin pigmentation increased in all treated patients, as confirmed by spectrophotometry. During continuous treatment, the current results indicate that elevated tanning intensity levels may stabilize over time. Lips and nevi also darkened. In red-haired study participants, hair color changed to brown after initiation of setmelanotide treatment. Discussion: Setmelanotide treatment leads to skin tanning and occasionally hair color darkening in both POMC- and LEPR-deficient patients. No malignant skin changes were observed in the patients of this study. However, the results highlight the importance of regular skin examinations before and during MC4R agonist treatment.

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Amiloride sensitive Na+ channel expression in the ileum after total colectomy in rats

Gastroenterology ◽

10.1016/0016-5085(95)28234-3 ◽

1995 ◽

Vol 108 (4) ◽

pp. A982

Author(s):

K. Koyama ◽

I. Sasaki ◽

Y. Funayama ◽

H. Naito ◽

T. Tsuchiya ◽

...

Keyword(s):

Total Colectomy ◽

Na Channel ◽

Channel Expression

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Abstract 5676: Elevated Oxidative Stress is Associated with Ventricular Fibrillation Episode in Patients with Brugada Syndrome without SCN5A Mutation

Circulation ◽

10.1161/circ.118.suppl_18.s_982-b ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Masamichi Tanaka ◽

Keiko Ohgou ◽

Koji Nakagawa ◽

Takeshi Tada ◽

Masato Murakami ◽

...

Keyword(s):

Oxidative Stress ◽

Risk Factor ◽

Ventricular Fibrillation ◽

Brugada Syndrome ◽

Endomyocardial Biopsy ◽

Heart Diseases ◽

Multivariable Analysis ◽

Pathophysiological Mechanism ◽

Normal Heart ◽

Scn5a Mutation

Background; Brugada Syndrome (BS) is a disease known to cause ventricular fibrillation (VF) with structurally normal heart. Gene mutation (i.e. SCN5A) has been proposed to be related to the development of BS and VF. However, the pathophysiological mechanism associated with VF development without SCN5A mutation has not been studied yet. Oxidative stress is a common disorder that is related to many heart diseases. We have previously demonstrated that oxidative stress is closely linked to the arrhythmic development. Accordingly, we examined 4-hydroxy-2-nonenal (HNE) modified protein, which is a common mediator of oxidative stress in the myocardium, and VF episodes in patients with BS. Methods; We collected sixty-eight BS patients that underwent right ventricular endomyocardial biopsy (66 males, 2 female; mean age 49.0±11.6 years old). VF was documented in 11 and SCN5A mutation was detected in 14 patients. Biopsy samples were processed for histology [Masson’s trichrome staining for fibrosis, immuno staining for CD45, CD68, and HNE modified protein]. All results from histology were compared with VF episodes. We also performed the analysis in VF patients with (n=14) or without SCN5A mutations (n=54). Results: HNE positive area was significantly larger in VF patients [VF(+): 16.3±10.5, VF(−): 9.3±5.7%: P=0.029]. All other parameters (fibrosis area, CD45, and CD68) were not different between the groups. In multivariable analysis, HNE positive area was most important risk factor of VF development in patients without SCN5A mutation (P=0.004). Conclusions ; These data suggested that oxidative stress is associated with VF development in BS patients, especially in patients without SCN5A mutation.

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CRISPR Knockdown of Kcnq3 Attenuates the M-current in NPY/AgRP Neurons

10.1101/2020.05.28.122341 ◽

2020 ◽

Author(s):

Todd L. Stincic ◽

Martha A. Bosch ◽

Avery C. Hunker ◽

Barbara Juarez ◽

Ashley M. Connors ◽

...

Keyword(s):

Arcuate Nucleus ◽

Energy State ◽

Input Resistance ◽

Field Testing ◽

Ingestive Behavior ◽

Loss Of Function ◽

Guide Rna ◽

M Current ◽

Subunit Mrna ◽

Channel Expression

AbstractArcuate nucleus Neuropeptide Y/Agouti-related peptide (NPY/AgRP) neurons drive ingestive behavior in response to the internal and external environment of an organism. NPY/AgRP neurons are adjacent to the median eminence, a circumventricular organ, and circulating metabolic factors and hormones communicate the energy state of the animal via these neurons by altering the excitability of NPY/AgRP neurons, which produces an appropriate change in behavior to maintain homeostasis. One example of this plasticity is seen in the M-current, a subthreshold, non-inactivating K+ current that acts to modulate excitability. Fasting decreases while estradiol increases the M-current through regulation of subunit mRNA expression of Kcnq 2, 3, & 5. KCNQ2/3 heteromers are thought to mediate the majority of the M-current. Here we used a recently developed single adeno-associated viral (AAV) vector containing a recombinase-dependent Staphylococcus aureus Cas9 (SaCas9) and a single guide RNA against Kcnq3 to selectively delete Kcnq3 in NPY/AgRP neurons to produce a loss of function in the M-current. We found that this virus was effective at knocking down Kcnq3 but not Kcnq2 expression. With the reduced KCNQ3 channel expression NPY/AgRP neurons were more depolarized, exhibited a higher input resistance, and the rheobase current needed to induce firing was significantly reduced, indicative of increased excitability. Although the resulting decrease in the M-current did not overtly alter ingestive behavior, it did significantly reduce the locomotor activity as measured in open field testing. Therefore, the SaCas9-sgKcnq3 is efficient to knock down Kcnq3 expression thereby reducing the M-current and increasing the excitability of NPY/AgRP neurons.

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