Early-Onset Atrial Fibrillation and the Prevalence of Rare Variants in Cardiomyopathy and Arrhythmia Genes

Yoneda, Zachary T.; Anderson, Katherine; Quintana, J.; O’Neill, Matthew J.; Sims, Richard A.; Glazer, Andrew M.; Shaffer, Christian M.; Crawford, Diane M.; Stricker, Thomas; Ye, Fei; Wells, Quinn S.; Stevenson, Lynne Warner; Michaud, Gregory F.; Darbar, Dawood; Lubitz, Steven A.; Ellinor, Patrick T.; Roden, Dan M.; Shoemaker, M. Benjamin

doi:10.1001/jamacardio.2021.3370

Cited by 101 publications

(94 citation statements)

References 52 publications

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“…This risk likely comes from two mechanisms. First, rare monogenic mutations in channels and gap junction proteins with large effect sizes occur in families with AF [ 34 ] and are more common in early-onset AF [ 35 ]. This includes germline mutations that pass to descendants as well as somatic mutations.…”

Section: Pathophysiology Of Af At the Genetic Levelmentioning

confidence: 99%

“…This includes germline mutations that pass to descendants as well as somatic mutations. When identified, such features motivate family screening to identify early-onset AF [ 35 ]. Second, common variations in a network of over 100 genes now identified from genome-wide association studies (GWAS) confer a smaller, yet additive, risk for AF [ 36 ].…”

Section: Pathophysiology Of Af At the Genetic Levelmentioning

confidence: 99%

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Identifying Atrial Fibrillation Mechanisms for Personalized Medicine

Deb

Ganesan

Feng

et al. 2021

JCM

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Atrial fibrillation (AF) is a major cause of heart failure and stroke. The early maintenance of sinus rhythm has been shown to reduce major cardiovascular endpoints, yet is difficult to achieve. For instance, it is unclear how discoveries at the genetic and cellular level can be used to tailor pharmacotherapy. For non-pharmacologic therapy, pulmonary vein isolation (PVI) remains the cornerstone of rhythm control, yet has suboptimal success. Improving these therapies will likely require a multifaceted approach that personalizes therapy based on mechanisms measured in individuals across biological scales. We review AF mechanisms from cell-to-organ-to-patient from this perspective of personalized medicine, linking them to potential clinical indices and biomarkers, and discuss how these data could influence therapy. We conclude by describing approaches to improve ablation, including the emergence of several mapping systems that are in use today.

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Section: Pathophysiology Of Af At the Genetic Levelmentioning

confidence: 99%

Section: Pathophysiology Of Af At the Genetic Levelmentioning

confidence: 99%

Identifying Atrial Fibrillation Mechanisms for Personalized Medicine

Deb

Ganesan

Feng

et al. 2021

JCM

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“…However, in the thin filament subgroup, AF tends to onset at younger age ( Bongini et al, 2016 ) and is more often aggressively treated with catheter ablation ( Coppini et al, 2014 ). Indeed, in a recent prospective observational cohort study on more than 1,200 patients with early-onset AF (<66 years) ( Yoneda et al, 2021 ), the cardiomyopathy-gene panel test identified a pathogenic sarcomere mutation in 10% of patients. This pivotal study supports the use of genetic testing in early-onset AF, although the clinical association between sarcomere mutation and AF remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Genotype-Driven Pathogenesis of Atrial Fibrillation in Hypertrophic Cardiomyopathy: The Case of Different TNNT2 Mutations

et al. 2022

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Atrial dilation and atrial fibrillation (AF) are common in Hypertrophic CardioMyopathy (HCM) patients and associated with a worsening of prognosis. The pathogenesis of atrial myopathy in HCM remains poorly investigated and no specific association with genotype has been identified. By re-analysis of our cohort of thin-filament HCM patients (Coppini et al. 2014) AF was identified in 10% of patients with sporadic mutations in the cardiac Troponin T gene (TNNT2), while AF occurrence was much higher (25–75%) in patients carrying specific “hot-spot” TNNT2 mutations. To determine the molecular basis of arrhythmia occurrence, two HCM mouse models expressing human TNNT2 variants (a “hot-spot” one, R92Q, and a “sporadic” one, E163R) were selected according to the different pathophysiological pathways previously demonstrated in ventricular tissue. Echocardiography studies showed a significant left atrial dilation in both models, but more pronounced in the R92Q. In E163R atrial trabeculae, in line with what previously observed in ventricular preparations, the energy cost of tension generation was markedly increased. However, no changes of twitch amplitude and kinetics were observed, and there was no atrial arrhythmic propensity. R92Q atrial trabeculae, instead, displayed normal ATP consumption but markedly increased myofilament calcium sensitivity, as previously observed in ventricular preparations. This was associated with reduced inotropic reserve and slower kinetics of twitch contractions and, importantly, with an increased occurrence of spontaneous beats and triggered contractions that represent an intrinsic arrhythmogenic mechanism promoting AF. The association of specific TNNT2 mutations with AF occurrence depends on the mutation-driven pathomechanism (i.e., increased atrial myofilament calcium sensitivity rather than increased myofilament tension cost) and may influence the individual response to treatment.

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“…5 They found 3.1% had a loss-of-function variant in a cardiomyopathy-associated gene. In a larger study of young-onset (<66 years) but otherwise unselected AF patients, 6 the yield of disease-associated variants in cardiomyopathy and arrhythmia syndrome genes was 10.1%, increasing to 16.8% in those aged <30 years at the time of presentation with AF. The most commonly implicated genes were all associated with cardiomyopathy ( TTN [29%], MYH7 [14%], MYH6 [8%], and LMNA [6%]).…”

mentioning

confidence: 94%