Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Puertas, Rosa Doñate; Millat, Gilles; Ernens, Isabelle; Gache, Vincent; Chauveau, Samuel; Morel, E.; Christin, Emilie; Couturier, Nathalie; Devaux, Yvan; Chevalier, Philippe

doi:10.1155/2018/4862480

Cited by 10 publications

(5 citation statements)

References 59 publications

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“…The myocardial hypertrophy commonly observed in high performance athletes may degenerate in fibrosis remodeling [64]. Furthermore, the severity extent in which fibrosis affects the cardiac function can be submitted to the interaction with multiple factors, such as, genetic conditions [65], gender [66] and ageing [67]. Moreover, in an AF scenario, the presence of fibrosis is expected to increase the proarrhythmic risk [15,18,[68][69][70].…”

Section: Discussionmentioning

confidence: 99%

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

Palacio

Ugarte

Sáiz

et al. 2021

Cells

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Remodeling in atrial fibrillation (AF) underlines the electrical and structural changes in the atria, where fibrosis is a hallmark of arrhythmogenic structural alterations. Fibrosis is an important feature of the AF substrate and can lead to abnormal conduction and, consequently, mechanical dysfunction. The fibrotic process comprises the presence of fibrotic cells, including fibroblasts, myofibroblasts and fibrocytes, which play an important role during fibrillatory dynamics. This work assesses the effect of the diffuse fibrosis density and the intermingled presence of the three types of fibrotic cells on the dynamics of persistent AF. For this purpose, the three fibrotic cells were electrically coupled to cardiomyocytes in a 3D realistic model of human atria. Low (6.25%) and high (25%) fibrosis densities were implemented in the left atrium according to a diffuse fibrosis representation. We analyze the action potential duration, conduction velocity and fibrillatory conduction patterns. Additionally, frequency analysis was performed in 50 virtual electrograms. The tested fibrosis configurations generated a significant conduction velocity reduction, where the larger effect was observed at high fibrosis density (up to 82% reduction in the fibrocytes configuration). Increasing the fibrosis density intensifies the vulnerability to multiple re-entries, zigzag propagation, and chaotic activity in the fibrillatory conduction. The most complex propagation patterns were observed at high fibrosis densities and the fibrocytes are the cells with the largest proarrhythmic effect. Left-to-right dominant frequency gradients can be observed for all fibrosis configurations, where the fibrocytes configuration at high density generates the most significant gradients (up to 4.5 Hz). These results suggest the important role of different fibrotic cell types and their density in diffuse fibrosis on the chaotic propagation patterns during persistent AF.

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Section: Discussionmentioning

confidence: 99%

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

Palacio

Ugarte

Sáiz

et al. 2021

Cells

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“…12,13 AKAP9 encodes for a scaffolding protein (A-kinase anchor protein 9) and is related to LQTS, BS, cardiomyopathy, atrial fibrillation, severe ventricular arrhythmia, and SUD. [14][15][16] Case 2 (family 2, II:1) with SUD had 3 missense VUS in the KCND3, AKAP9, and KCNE1 genes. The KCND3 gene encodes a member of the potassium channel, Potassium Voltage-Gated Channel Subfamily D Member 3.…”

Section: Discussionmentioning

confidence: 99%

“…RANGRF mutations were related to BS and histiocytoid cardiomyopathy in the literature 12,13 . AKAP9 encodes for a scaffolding protein (A-kinase anchor protein 9) and is related to LQTS, BS, cardiomyopathy, atrial fibrillation, severe ventricular arrhythmia, and SUD 14–16 …”

Section: Discussionmentioning

confidence: 99%

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

Turkgenc,

Baydar,

Deniz

et al. 2023

Applied Immunohistochemistry &Amp; Molecular Morphology

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Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43_ c.1000+2T>C splice site mutation and the SCN5A_ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4, RANGRF, AKAP9, KCND3, KCNE1, DSG2, CASQ1, and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

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“…In a cohort of 94 patients with AF, a study screening for rare variants involved in atrial myopathy revealed a higher rate of variant carriers in patients presenting with atrial dilation. 66 Recent investigations strongly support the relevance of broader genetic background to atrial remodeling. 78,79 Atrial Features: Some Special Considerations…”

Section: Primary Atrial Structural Remodelingmentioning

confidence: 92%

Genetic Atrial Cardiomyopathies: Common Features, Specific Differences, and Broader Relevance to Understanding Atrial Cardiomyopathy

Marcoux,

Sosnowski,

Ninni

et al. 2023

Circ: Arrhythmia and Electrophysiology

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Atrial cardiomyopathy is a condition that causes electrical and contractile dysfunction of the atria, often along with structural and functional changes. Atrial cardiomyopathy most commonly occurs in conjunction with ventricular dysfunction, in which case it is difficult to discern the atrial features that are secondary to ventricular dysfunction from those that arise as a result of primary atrial abnormalities. Isolated atrial cardiomyopathy (atrial-selective cardiomyopathy [ASCM], with minimal or no ventricular function disturbance) is relatively uncommon and has most frequently been reported in association with deleterious rare genetic variants. The genes involved can affect proteins responsible for various biological functions, not necessarily limited to the heart but also involving extracardiac tissues. Atrial enlargement and atrial fibrillation are common complications of ASCM and are often the predominant clinical features. Despite progress in identifying disease-causing rare variants, an overarching understanding and approach to the molecular pathogenesis, phenotypic spectrum, and treatment of genetic ASCM is still lacking. In this review, we aim to analyze the literature relevant to genetic ASCM to understand the key features of this rather rare condition, as well as to identify distinct characteristics of ASCM and its arrhythmic complications that are related to specific genotypes. We outline the insights that have been gained using basic research models of genetic ASCM in vitro and in vivo and correlate these with patient outcomes. Finally, we provide suggestions for the future investigation of patients with genetic ASCM and improvements to basic scientific models and systems. Overall, a better understanding of the genetic underpinnings of ASCM will not only provide a better understanding of this condition but also promises to clarify our appreciation of the more commonly occurring forms of atrial cardiomyopathy associated with ventricular dysfunction.

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Atrial Structural Remodeling Gene Variants in Patients with Atrial Fibrillation

Cited by 10 publications

References 59 publications

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

The Effects of Fibrotic Cell Type and Its Density on Atrial Fibrillation Dynamics: An In Silico Study

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy

Genetic Atrial Cardiomyopathies: Common Features, Specific Differences, and Broader Relevance to Understanding Atrial Cardiomyopathy

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