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Molecular Study of Cardiac Death

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: closed (15 January 2023) | Viewed by 9563

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Prof. Dr. Sorin Hostiuc

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Department of Legal Medicine and Bioethics, Faculty of Dental Medicine, “Carol Davila University” of Medicine and Pharmacy, RO-020021 Bucharest, Romania
Interests: pathology; bioethics; sudden cardiac death; forensic; research ethics; telocytes; stem cells; organoids
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Special Issue Information

Dear Colleagues,

Cardiovascular diseases remain one of the most important causes of mortality worldwide, despite the significant advances made in the last few decades in the field. Sudden cardiac death disproportionately affects the young, and its causes often remain unknown.

This Special Issue aims to bring recent advances in molecular biology that could be used to tackle sudden death due to cardiovascular diseases. We welcome articles detailing underlying physiopathological mechanisms for various causes of sudden death, including (but not limited to) ion channel disease, arrhythmogenic disorders, congenital heart diseases, cardiac conduction system disorders, etc. We are also interested in studies that aim to develop updated or new techniques for diagnosing these disorders, both in the clinic and during autopsies including (but not limited to) molecular autopsy of the heart, advanced micro-imaging techniques, genetic diagnosis, and advanced histological techniques. Due to its increasing importance, including in molecular biology, we especially welcome meta-analyses or studies using big data mining, which could bring new insights in the area.

Prof. Dr. Sorin Hostiuc
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

sudden cardiac death
molecular biology
immunohistochemistry
molecular autopsy

Published Papers (5 papers)

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Research

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15 pages, 3162 KiB

Open AccessArticle

Molecular and Functional Relevance of Na_V1.8-Induced Atrial Arrhythmogenic Triggers in a Human SCN10A Knock-Out Stem Cell Model

by Nico Hartmann, Maria Knierim, Wiebke Maurer, Nataliya Dybkova, Gerd Hasenfuß, Samuel Sossalla and Katrin Streckfuss-Bömeke

Int. J. Mol. Sci. 2023, 24(12), 10189; https://doi.org/10.3390/ijms241210189 - 15 Jun 2023

Cited by 1 | Viewed by 1230

Abstract

In heart failure and atrial fibrillation, a persistent Na⁺ current (I_NaL) exerts detrimental effects on cellular electrophysiology and can induce arrhythmias. We have recently shown that Na_V1.8 contributes to arrhythmogenesis by inducing a I_NaL. Genome-wide association studies indicate that mutations in the SCN10A gene (Na_V1.8) are associated with increased risk for arrhythmias, Brugada syndrome, and sudden cardiac death. However, the mediation of these Na_V1.8-related effects, whether through cardiac ganglia or cardiomyocytes, is still a subject of controversial discussion. We used CRISPR/Cas9 technology to generate homozygous atrial SCN10A-KO-iPSC-CMs. Ruptured-patch whole-cell patch-clamp was used to measure the I_NaL and action potential duration. Ca²⁺ measurements (Fluo 4-AM) were performed to analyze proarrhythmogenic diastolic SR Ca²⁺ leak. The I_NaL was significantly reduced in atrial SCN10A KO CMs as well as after specific pharmacological inhibition of Na_V1.8. No effects on atrial APD₉₀ were detected in any groups. Both SCN10A KO and specific blockers of Na_V1.8 led to decreased Ca²⁺ spark frequency and a significant reduction of arrhythmogenic Ca²⁺ waves. Our experiments demonstrate that Na_V1.8 contributes to I_NaL formation in human atrial CMs and that Na_V1.8 inhibition modulates proarrhythmogenic triggers in human atrial CMs and therefore Na_V1.8 could be a new target for antiarrhythmic strategies. Full article

(This article belongs to the Special Issue Molecular Study of Cardiac Death)

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16 pages, 2782 KiB

Open AccessArticle

Unpredicted Aberrant Splicing Products Identified in Postmortem Sudden Cardiac Death Samples

by Monica Coll, Anna Fernandez-Falgueras, Anna Iglesias, Bernat del Olmo, Laia Nogue-Navarro, Adria Simon, Alexandra Perez Serra, Marta Puigmule, Laura Lopez, Ferran Pico, Monica Corona, Marta Vallverdu-Prats, Coloma Tiron, Oscar Campuzano, Josep Castella, Ramon Brugada and Mireia Alcalde

Int. J. Mol. Sci. 2022, 23(20), 12640; https://doi.org/10.3390/ijms232012640 - 20 Oct 2022

Cited by 1 | Viewed by 1300

Abstract

Molecular screening for pathogenic mutations in sudden cardiac death (SCD)-related genes is common practice for SCD cases. However, test results may lead to uncertainty because of the identification of variants of unknown significance (VUS) occurring in up to 70% of total identified variants due to a lack of experimental studies. Genetic variants affecting potential splice site variants are among the most difficult to interpret. The aim of this study was to examine rare intronic variants identified in the exonic flanking sequence to meet two main objectives: first, to validate that canonical intronic variants produce aberrant splicing; second, to determine whether rare intronic variants predicted as VUS may affect the splicing product. To achieve these objectives, 28 heart samples of cases of SCD carrying rare intronic variants were studied. Samples were analyzed using 85 SCD genes in custom panel sequencing. Our results showed that rare intronic variants affecting the most canonical splice sites displayed in 100% of cases that they would affect the splicing product, possibly causing aberrant isoforms. However, 25% of these cases (1/4) showed normal splicing, contradicting the in silico results. On the contrary, in silico results predicted an effect in 0% of cases, and experimental results showed >20% (3/14) unpredicted aberrant splicing. Thus, deep intron variants are likely predicted to not have an effect, which, based on our results, might be an underestimation of their effect and, therefore, of their pathogenicity classification and family members’ follow-up. Full article

(This article belongs to the Special Issue Molecular Study of Cardiac Death)

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16 pages, 2049 KiB

Open AccessArticle

Premature Termination Codon in 5′ Region of Desmoplakin and Plakoglobin Genes May Escape Nonsense-Mediated Decay through the Reinitiation of Translation

by Marta Vallverdú-Prats, Ramon Brugada and Mireia Alcalde

Int. J. Mol. Sci. 2022, 23(2), 656; https://doi.org/10.3390/ijms23020656 - 07 Jan 2022

Cited by 3 | Viewed by 2050

Abstract

Arrhythmogenic cardiomyopathy is a heritable heart disease associated with desmosomal mutations, especially premature termination codon (PTC) variants. It is known that PTC triggers the nonsense-mediated decay (NMD) mechanism. It is also accepted that PTC in the last exon escapes NMD; however, the mechanisms involving NMD escaping in 5′-PTC, such as reinitiation of translation, are less known. The main objective of the present study is to evaluate the likelihood that desmosomal genes carrying 5′-PTC will trigger reinitiation. HL1 cell lines were edited by CRISPR/Cas9 to generate isogenic clones carrying 5′-PTC for each of the five desmosomal genes. The genomic context of the ATG in-frame in the 5′ region of desmosomal genes was evaluated by in silico predictions. The expression levels of the edited genes were assessed by Western blot and real-time PCR. Our results indicate that the 5′-PTC in PKP2, DSG2 and DSC2 acts as a null allele with no expression, whereas in the DSP and JUP gene, N-truncated protein is expressed. In concordance with this, the genomic context of the 5′-region of DSP and JUP presents an ATG in-frame with an optimal context for the reinitiation of translation. Thus, 5′-PTC triggers NMD in the PKP2, DSG2* and DSC2 genes, whereas it may escape NMD through the reinitiation of the translation in DSP and JUP genes, with no major effects on ACM-related gene expression. Full article

(This article belongs to the Special Issue Molecular Study of Cardiac Death)

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Review

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10 pages, 2410 KiB

Open AccessReview

Identification of Risk Genes Associated with Myocardial Infarction—Big Data Analysis and Literature Review

by Cosmin Tirdea, Sorin Hostiuc, Horatiu Moldovan and Alexandru Scafa-Udriste

Int. J. Mol. Sci. 2022, 23(23), 15008; https://doi.org/10.3390/ijms232315008 - 30 Nov 2022

Cited by 9 | Viewed by 1646

Abstract

Acute myocardial infarction occurs when blood supply to a particular coronary artery is cut off, causing ischemia or hypoxia and subsequent heart muscle destruction in the vascularized area. With a mortality rate of 17% per year, myocardial infarction (MI) is still one of the top causes of death globally. Numerous studies have been done to identify the genetic risk factors for myocardial infarction, as a positive family history of heart disease is one of the most potent cardiovascular risk factors. The goal of this review is to compile all the information currently accessible in the literature on the genes associated with AMI. We performed a big data analysis of genes associated with acute myocardial infarction, using the following keywords: “myocardial infarction”, “genes”, “involvement”, “association”, and “risk”. The analysis was done using PubMed, Scopus, and Web of Science. Data from the title, abstract, and keywords were exported as text files and imported into an Excel spreadsheet. Its analysis was carried out using the VOSviewer v. 1.6.18 software. Our analysis found 28 genes which are mostly likely associated with an increased risk for AMI, including: PAI-1, CX37, IL18, and others. Also, a correlation was made between the results obtained in the big data analysis and the results of the review. The most important genes increasing the risk for AMI are lymphotoxin-a gene (LTA), LGALS2, LDLR, and APOA5. A deeper understanding of the underlying functional genomic circuits may present new opportunities for research in the future. Full article

(This article belongs to the Special Issue Molecular Study of Cardiac Death)

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16 pages, 1152 KiB

Open AccessReview

Promising Therapies for Atrial Fibrillation and Ventricular Tachycardia

by Andrei Alexandru Mircea, Mihaela Rusu, Elisa Anamaria Liehn and Octavian Bucur

Int. J. Mol. Sci. 2022, 23(20), 12612; https://doi.org/10.3390/ijms232012612 - 20 Oct 2022

Cited by 2 | Viewed by 2460

Abstract

Sudden cardiac death due to arrhythmias, such as atrial fibrillation or ventricular tachycardia, account for 15–20% of all deaths. Myocardial infarction increases the burden of atrial fibrillation and ventricular tachycardia by structural and electrical remodeling of the heart. The current management of new-onset atrial fibrillation includes electric cardioversion with very high conversion rates and pharmacologic cardioversion, with less a than 50% conversion rate. If atrial fibrillation cannot be converted, the focus becomes the control of the symptoms ensuring a constant rhythm and rate control, without considering other contributory factors such as autonomic imbalance. Recently, a huge success was obtained by developing ablation techniques or addressing the vagal nerve stimulation. On the other hand, ventricular tachycardia is more sensitive to drug therapies. However, in cases of non-responsiveness to drugs, the usual therapeutic choice is represented by stereotactic ablative therapy or catheter ablation. This review focuses on these newly developed strategies for treatment of arrhythmias in clinical practice, specifically on vernakalant and low-level tragus stimulation for atrial fibrillation and stereotactic ablative therapy for drug-refractory ventricular tachycardia. These therapies are important for the significant improvement of the management of atrial fibrillation and ventricular tachycardia, providing: (1) a safer profile than current therapies, (2) higher success rate than current solutions, (3) low cost of delivery. Full article

(This article belongs to the Special Issue Molecular Study of Cardiac Death)

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