Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

Wijk, Stan W. van; Su, Wei; Wijdeveld, Leonoor F. J. M.; Ramos, Kennedy Silva; Brundel, Bianca J. J. M.

doi:10.3390/cells11030416

Cited by 8 publications

(6 citation statements)

References 131 publications

(151 reference statements)

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“…With the incidence of AF increasing over the years, it is crucial to explore the various risk factors of AF. Previous studies have demonstrated the significant contribution of cytoskeletal protein variants and calcium ions in the development of AF from a molecular biological perspective [ 44 , 45 , 46 ]. And in the present research, we focus on the role of a higher BWM in the onset of AF.…”

Section: Discussionmentioning

confidence: 99%

Genetic Predisposition to a Higher Whole Body Water Mass May Increase the Risk of Atrial Fibrillation: A Mendelian Randomization Study

Zhu

Chen

Tian

et al. 2023

JCDD

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Background: Observational studies have found an association between increased whole body water mass (BWM) and atrial fibrillation (AF). However, the causality has yet to be confirmed. To provide feasible protective measures on disease development, we performed Mendelian randomization (MR) design to estimate the potential causal relationship between increased BWM and AF. Methods: We implemented a two-sample MR study to assess whether increased BWM causally influences AF incidence. For exposure, 61 well-powered genetic instruments extracted from UK Biobank (N = 331,315) were used as the proxies of BWM. Summary genetic data of AF were obtained from FinnGen (Ncase = 22,068; Ncontrol = 116,926). Inverse-variance weighted (IVW), MR-Egger and weighted median methods were selected to infer causality, complemented with a series of sensitivity analyses. MR-Pleiotropy Residual Sum and Outlier (MR-PRESSO) and Radial MR were employed to identify outliers. Furthermore, risk factor analyses were performed to investigate the potential mechanisms between increased BWM and AF. Results: Genetic predisposition to increased BWM was demonstrated to be significantly associated with AF in the IVW model (OR = 2.23; 95% CI = 1.47–3.09; p = 1.60 × 10−7), and the result was consistent in other MR approaches. There was no heterogeneity or pleiotropy detected in sensitivity analysis. MR-PRESSO identified no outliers with potential pleiotropy after excluding outliers by Radial MR. Furthermore, our risk factor analyses supported a positive causal effect of genetic predicted increased BWM on edematous diseases. Conclusions: MR estimates showed that a higher BWM could increase the risk of AF. Pathological edema is an important intermediate link mediating this causal relationship.

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Section: Discussionmentioning

confidence: 99%

Genetic Predisposition to a Higher Whole Body Water Mass May Increase the Risk of Atrial Fibrillation: A Mendelian Randomization Study

Zhu

Chen

Tian

et al. 2023

JCDD

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“…For instance, MYH6 encodes the α-subunit of myosin heavy chain predominantly expressed in atrium. Myosin, an ATPase cellular motor protein whose heavy chain subunit is a main component (31,32). MYL4 is a chamberspecific expression restricted to the atria, which encodes atrial Light Chain-1, a key sarcomeric component.…”

Section: Pathophysiological Mechanisms Of Af Remodelling In Hcmmentioning

confidence: 99%

“…The overexpression of MYH6 in HL-1 and isolated rat atrial cardiomyocytes results in sarcomere impairment, electrophysiological abnormalities, and a slower conduction velocity, suggesting the potential role of MYH6 gene variants in atrial structure and function. Comparable pathways may play a role in mutant MYH6-induced AF ( 31 , 32 ). MYL4 is a chamber-specific expression restricted to the atria, which encodes atrial Light Chain-1, a key sarcomeric component.…”

Section: Pathophysiological Mechanisms Of Af Remodelling In Hcmmentioning

confidence: 99%

Genetic variants, pathophysiological pathways, and oral anticoagulation in patients with hypertrophic cardiomyopathy and atrial fibrillation

Wang

Chen

Liu

et al. 2023

Front. Cardiovasc. Med.

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Atrial fibrillation (AF) is commonly prevalent in patients with hypertrophic cardiomyopathy (HCM). However, whether the prevalence and incidence of AF are different between genotype-positive vs. genotype-negative patients with HCM remains controversial. Recent evidence has indicated that AF is often the first presentation of genetic HCM patients in the absence of a cardiomyopathy phenotype, implying the importance of genetic testing in this population with early-onset AF. However, the association of the identified sarcomere gene variants with HCM occurrence in the future remains unclear. How the identification of these cardiomyopathy gene variants should influence the use of anticoagulation therapy for a patient with early-onset AF is still undefined. In this review, we sought to assess the genetic variants, pathophysiological pathways, and oral anticoagulation in patients with HCM and AF.

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“…The clinical spectrum of desminopathies is broad and even within the same family different types of cardiomyopathies may result [15]. Ventricular and atrial arrhythmias are frequently observed in patients with desminopathies [16][17][18][19] leading in some cases to cardiac arrest or even sudden cardiac death [20,21].…”

Section: Introductionmentioning

confidence: 99%

Atlas ofDES(desmin) variants: Impact of variants located within the head domain on filament assembly

Voß,

Walhorn,

Holler

et al. 2023

Preprint

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Desmin is a muscle-specific intermediate filament protein, which plays a significant role in providing structural integrity of cardiomyocytes by connecting different cell organelles and multi-protein complexes. DES mutations cause cardiomyopathies and skeletal myopathies. Most of these pathogenic mutations are localized in the highly conserved rod domain and affect the filament assembly. However, the impact of DES variants within the N-terminal head domain on the filament assembly process is widely unknown. Therefore, we inserted a set of 85 different head domain variants with unknown significance from human genetic databases in expression constructs and investigated their impact on filament formation in cell culture in combination with confocal microscopy. The majority of these desmin variants do not affect the filament assembly. However, the desmin variants -p.S13P, -p.N107D, -p.E108G and -p.K109E significantly inhibit the filament assembly. Additionally, we expressed and purified recombinant desmin and investigated the filament assembly defects by atomic force microscopy verifying these findings at the single molecular level. Furthermore, we truncated systematically the head domain to investigate which general parts of this domain are necessary for filament assembly. In summary, our functional investigations might be relevant for the classification of novel DES variants and the genetic counselling of patients carrying desmin head variants.

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Cytoskeletal Protein Variants Driving Atrial Fibrillation: Potential Mechanisms of Action

Cited by 8 publications

References 131 publications

Genetic Predisposition to a Higher Whole Body Water Mass May Increase the Risk of Atrial Fibrillation: A Mendelian Randomization Study

Genetic Predisposition to a Higher Whole Body Water Mass May Increase the Risk of Atrial Fibrillation: A Mendelian Randomization Study

Genetic variants, pathophysiological pathways, and oral anticoagulation in patients with hypertrophic cardiomyopathy and atrial fibrillation

Atlas ofDES(desmin) variants: Impact of variants located within the head domain on filament assembly

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