Electrophysiologic and molecular mechanisms of a frameshift NPPA mutation linked with familial atrial fibrillation

AbstractThe molecular mechanisms underlying atrial fibrillation (AF), the most common form of arrhythmia, are poorly understood and therefore target-specific treatment options remain an unmet clinical need. Excitation–contraction coupling in cardiac myocytes requires high amounts of adenosine triphosphate (ATP), which is replenished by oxidative phosphorylation in mitochondria. Calcium (Ca2+) is a key regulator of mitochondrial function by stimulating the Krebs cycle, which produces nicotinamide adenine dinucleotide for ATP production at the electron transport chain and nicotinamide adenine dinucleotide phosphate for the elimination of reactive oxygen species (ROS). While it is now well established that mitochondrial dysfunction plays an important role in the pathophysiology of heart failure, this has been less investigated in atrial myocytes in AF. Considering the high prevalence of AF, investigating the role of mitochondria in this disease may guide the path towards new therapeutic targets. In this review, we discuss the importance of mitochondrial Ca2+ handling in regulating ATP production and mitochondrial ROS emission and how alterations, particularly in these aspects of mitochondrial activity, may play a role in AF. In addition to describing research advances, we highlight areas in which further studies are required to elucidate the role of mitochondria in AF.

Download Full-text

Familial atrial rapid fibrillation associated with double mutations of SCN5A and KCNQ1

Cardiology in the Young ◽

10.1017/s1047951121000615 ◽

2021 ◽

pp. 1-3

Author(s):

Miwa Kanai ◽

Keiko Toyohara ◽

Morio Shoda

Keyword(s):

Atrial Fibrillation ◽

Paediatric Population ◽

Familial Case ◽

Familial Atrial Fibrillation

Abstract Familial atrial fibrillation is inherited and sporadically occurs in the paediatric population. Generally, fibrillated wavelets are reported at a frequency of approximately 6 Hz. Herein, we report a familial case presenting rapidly fibrillated wavelets at frequencies of approximately 12 to 30 Hz associated with KCNQ1 and SCN5A mutations.

Download Full-text

Abstract P780: Myosin Light Chain Dephosphorylation by Ppp1r12c Promotes Atrial Hypocontractility in Atrial Fibrillation

Stroke ◽

10.1161/str.52.suppl_1.p780 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Francisco J Gonzalez-Gonzalez ◽

Perike Srikanth ◽

Andrielle E Capote ◽

Alsina Katherina M ◽

Benjamin Levin ◽

...

Keyword(s):

Atrial Fibrillation ◽

Light Chain ◽

Myosin Light Chain ◽

Molecular Mechanisms ◽

Contractile Function ◽

Right Atrial ◽

Western Blots

Atrial fibrillation (AF) is the most common sustained arrhythmia, with an estimated prevalence in the U.S.of 6.1 million. AF increases the risk of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. We have recently identified protein phosphatase 1 subunit 12c (PPP1R12C) as a key molecule targeting myosin light-chain phosphorylation in AF. Objective: We hypothesize that the overexpression of PPP1R12C causes hypophosphorylation of atrial myosin light-chain 2 (MLC2a), thereby decreasing atrial contractility in AF. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluate the role of the PP1c-PPP1R12C interaction in MLC2a de-phosphorylation, we utilized Western blots, co-immunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A), PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, associated with a reduction in atrial contractility and an increase in AF inducibility. All these discoveries suggest that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Download Full-text

Abstract P458: Myosin Light Chain Dephosphorylation By Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation

Circulation Research ◽

10.1161/res.129.suppl_1.p458 ◽

2021 ◽

Vol 129 (Suppl_1) ◽

Author(s):

Francisco J Gonzalez-Gonzalez ◽

Srikanth Perike ◽

Frederick Damen ◽

Andrielle Capote ◽

Katherina M Alsina ◽

...

Keyword(s):

Atrial Fibrillation ◽

Light Chain ◽

Myosin Light Chain ◽

Molecular Mechanisms ◽

Contractile Function ◽

Right Atrial ◽

Western Blots

Introduction: Atrial fibrillation (AF), is the most common sustained arrhythmia, with an estimated prevalence in the U.S. of 2.7 million to 6.1 million and is predictive to increase to 12.1 million in 2030. AF increases the chances of a thromboembolic stroke in five-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function in AF remains unknown. Objective: The overexpression of PPP1R12C, causes hypophosphorylation of atrial myosin light chain 2 (MLC2a), decreasing atrial contractility. Methods and Results: Left and right atrial appendage tissues were isolated from AF patients versus sinus rhythm (SR). To evaluated the role of PP1c-PPP1R12C interaction in MLC2a de-phosphorylation we used Western blots, coimmunoprecipitation, and phosphorylation assays. In patients with AF, PPP1R12C expression was increased 3.5-fold versus SR controls with an 88% reduction in MLC2a phosphorylation. PPP1R12C-PP1c binding and PPP1R12C-MLC2a binding were significantly increased in AF. In vitro studies of either pharmacologic (BDP5290) or genetic (T560A) PPP1R12C activation demonstrated increased PPP1R12C binding with both PP1c and MLC2a, and dephosphorylation of MLC2a. Additionally, to evaluate the role of PPP1R12C expression in cardiac function, mice with lentiviral cardiac-specific overexpression of PPP1R12C (Lenti-12C) were evaluated for atrial contractility using echocardiography, versus wild-type and Lenti-controls. Lenti-12C mice demonstrated a 150% increase in left atrium size versus controls, with reduced atrial strain and atrial ejection fraction. Also, programmed electrical stimulation was performed to evaluate AF inducibility in vivo. Pacing-induced AF in Lenti-12C mice was significantly higher than controls. Conclusion: The Overexpression of PPP1R12C increases PP1c targeting to MLC2a and provokes dephosphorylation, that cause a reduction in atrial contractility and increases AF inducibility. All these discoveries advocate that PP1 regulation of sarcomere function at MLC2a is a main regulator of atrial contractility in AF.

Download Full-text

A Review of the Molecular Mechanisms Underlying Cardiac Fibrosis and Atrial Fibrillation

Journal of Clinical Medicine ◽

10.3390/jcm10194430 ◽

2021 ◽

Vol 10 (19) ◽

pp. 4430

Author(s):

Grażyna Sygitowicz ◽

Agata Maciejak-Jastrzębska ◽

Dariusz Sitkiewicz

Keyword(s):

Atrial Fibrillation ◽

Molecular Mechanisms ◽

Cardiac Fibrosis ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β1 ◽

Signalling Pathways ◽

Ang Ii ◽

Atrial Fibrosis ◽

Genes Encoding ◽

Tgf Β1

The cellular and molecular mechanism involved in the pathogenesis of atrial fibrosis are highly complex. We have reviewed the literature that covers the effectors, signal transduction and physiopathogenesis concerning extracellular matrix (ECM) dysregulation and atrial fibrosis in atrial fibrillation (AF). At the molecular level: angiotensin II, transforming growth factor-β1, inflammation, and oxidative stress are particularly important for ECM dysregulation and atrial fibrotic remodelling in AF. We conclude that the Ang-II-MAPK and TGF-β1-Smad signalling pathways play a major, central role in regulating atrial fibrotic remodelling in AF. The above signalling pathways induce the expression of genes encoding profibrotic molecules (MMP, CTGF, TGF-β1). An important mechanism is also the generation of reactive oxygen species. This pathway induced by the interaction of Ang II with the AT2R receptor and the activation of NADPH oxidase. Additionally, the interplay between cardiac MMPs and their endogenous tissue inhibitors of MMPs, is thought to be critical in atrial ECM metabolism and fibrosis. We also review recent evidence about the role of changes in the miRNAs expression in AF pathophysiology and their potential as therapeutic targets. Furthermore, keeping the balance between miRNA molecules exerting anti-/profibrotic effects is of key importance for the control of atrial fibrosis in AF.

Download Full-text

Abstract 1236: A Molecular and Functional Basis for Focal Arrhythmogenesis in Heart Failure-associated Atrial Fibrillation

Circulation ◽

10.1161/circ.116.suppl_16.ii_251-b ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Yung-Hsin Yeh ◽

Reza Wakili ◽

Xiao Yan Qi ◽

Denis Chartier ◽

Stefan Kääb ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Protein Expression ◽

Action Potentials ◽

Molecular Mechanisms ◽

Potential Role ◽

Regulatory Proteins ◽

Related Protein ◽

Triggered Activity ◽

Delayed Afterdepolarizations

Introduction: Heart failure (HF) frequently causes atrial fibrillation (AF) and focal sources of unknown mechanism have been implicated. Here, we studied the potential role and molecular mechanisms of Ca 2+ handling abnormalities. Methods: Ca 2+ handling (microfluorescence, Indo-1 AM) and related protein expression (Western blot) were assessed in left atria of 20 dogs with ventricular tachypacing (240 bpm × 2 wks)-induced HF and 20 controls (CTLs). Whole-cell perforated-patch was used to record action potentials (APs), delayed afterdepolarizations (DADs) and triggered activity. Results : HF increased [Ca 2+ ] i transient amplitude from 239±24 to 444±43* nM (*P<0.05), and [Ca 2+ ] i release by 10 mM local caffeine puffs (an index of SR Ca 2+ content) from 849±71 (CTL) to 1574±169* nM (HF). Spontaneous Ca 2+ release events increased from 1.8±0.5 (CTL) to 10.7±2.1* events/run (HF). HF significantly increased APD (by ~40% at 1 Hz). DADs and triggered activity were more common in HF (15.2±2.6 triggered APs/run, vs CTL 0.4±0.2*), and were abolished by ryanodine (10 μM), but not by the I f -blocker Cs + (2 mM). HF caused profound changes in protein expression of key Ca 2+ handling and regulatory proteins (Table ). Calsequestrin, the major SR Ca 2+ -binding protein, was reduced by 32%*. Fractional RYR2 PKA (Ser2809) phosphorylation decreased by 63%*, whereas CaMKII (Ser2815) RYR2 phosphorylation increased by 221%*. The catalytic and regulatory (RII) PKA subunits were downregulated by 15%* and 73%*, whereas expression and autophosphorylation (Thr287) of CaMKIIδ were increased by 45%* and 81%* respectively. NCX1, SERCA and total, PKA and CaMKII phosphorylated SERCA-regulatory phospholamban were unchanged by HF. Conclusions: HF causes profound changes in regulation and expression of atrial Ca 2+ handling proteins, producing increased SR Ca 2+ load and release, along with DADs and triggered activity that may account for focal mechanisms that initiate and/or sustain HF-related AF.

Download Full-text

Molecular Mechanisms, Diagnostic Aspects and Therapeutic Opportunities of Micro Ribonucleic Acids in Atrial Fibrillation

International Journal of Molecular Sciences ◽

10.3390/ijms21082742 ◽

2020 ◽

Vol 21 (8) ◽

pp. 2742 ◽

Cited By ~ 1

Author(s):

Allan Böhm ◽

Marianna Vachalcova ◽

Peter Snopek ◽

Ljuba Bacharova ◽

Dominika Komarova ◽

...

Keyword(s):

Gene Expression ◽

Atrial Fibrillation ◽

Molecular Mechanisms ◽

Wide Spectrum ◽

Regulation Of Gene Expression ◽

Review Article ◽

Ribonucleic Acids ◽

Rna Molecules ◽

Diagnostic Aspects ◽

Non Coding Rna

Micro ribonucleic acids (miRNAs) are short non-coding RNA molecules responsible for regulation of gene expression. They are involved in many pathophysiological processes of a wide spectrum of diseases. Recent studies showed their involvement in atrial fibrillation. They seem to become potential screening biomarkers for atrial fibrillation and even treatment targets for this arrhythmia. The aim of this review article was to summarize the latest knowledge about miRNA and their molecular relation to the pathophysiology, diagnosis and treatment of atrial fibrillation.

Download Full-text

Clinical profile and outcome of familial versus non-familial atrial fibrillation

International Journal of Cardiology ◽

10.1016/j.ijcard.2020.03.080 ◽

2020 ◽

Vol 314 ◽

pp. 70-74 ◽

Cited By ~ 1

Author(s):

Mona Heidarali ◽

Hooman Bakhshandeh ◽

Amirfarjam Fazelifar ◽

Majid Haghjoo

Keyword(s):

Atrial Fibrillation ◽

Clinical Profile ◽

Familial Atrial Fibrillation

Download Full-text

Comprehensive Analysis of Differential Immunocyte Infiltration and Potential ceRNA Networks Involved in the Development of Atrial Fibrillation

BioMed Research International ◽

10.1155/2020/8021208 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Jiafeng Wu ◽

Huiming Deng ◽

Qianghua Chen ◽

Qiang Wu ◽

Xiaolong Li ◽

...

Keyword(s):

Atrial Fibrillation ◽

Dna Methylation ◽

Left Atrial ◽

Molecular Mechanisms ◽

Linear Models ◽

Core Gene ◽

Differential Analysis ◽

Methylation Analysis ◽

Protein Protein Interaction ◽

Dna Methylation Analysis

This study is aimed at identifying potential molecular mechanisms and candidate biomarkers in the left atrial regions for the diagnosis and treatment of valvular atrial fibrillation (VAF). Multibioinformatics methods, including linear models for microarray analysis (LIMMA), an SVA algorithm, CIBERSORT immune infiltration, and DNA methylation analysis, were employed. In addition, the protein-protein interaction (PPI) network, Gene Ontology (GO), and molecular pathways of differentially expressed genes (DEGs) or differential methylation regions were constructed. In all, compared with the normal rhythm group, 243 different mRNAs (29 downregulated and 214 upregulated) and 26 different lncRNAs (3 downregulated and 23 upregulated) were detected in the left atrium (LA) of atrial fibrillation (AF) patients, and the neutrophil and CD8+ T cell were infiltrated. Additionally, 199 different methylation sites (107 downregulated and 92 upregulated) were also identified based on DNA methylation analysis. After integration, ELOVL2, CCR2, and WEE1 were detected for differentially methylated and differentially transcribed genes. Among them, WEE1 was also a core gene identified by the competing endogenous RNA (ceRNA) network that included WEE1-KRBOX1-AS1-hsa-miR-17-5p, in VAF left atrial tissue. We combined the DNA methylation and transcriptional expression differential analysis and found that WEE1 (cg13365543) may well be a candidate gene regulated by DNA methylation modification. Moreover, KRBOX1-AS1 and WEE1 can compete endogenously and may mediate myocardial tissue infiltration into CD8+ T cells and participate in the AF process.

Download Full-text