Atrial fibrillation (AF) affects more than 33 million individuals worldwide1 and has a complex heritability2. We conducted the largest meta-analysis of genome-wide association studies (GWAS) for AF to date, consisting of more than half a million individuals, including 65,446 with AF. In total, we identified 97 loci significantly associated with AF, including 67 that were novel in a combined-ancestry analysis, and 3 that were novel in a European-specific analysis. We sought to identify AF-associated genes at the GWAS loci by performing RNA-sequencing and expression quantitative trait locus analyses in 101 left atrial samples, the most relevant tissue for AF. We also performed transcriptome-wide analyses that identified 57 AF-associated genes, 42 of which overlap with GWAS loci. The identified loci implicate genes enriched within cardiac developmental, electrophysiological, contractile and structural pathways. These results extend our understanding of the biological pathways underlying AF and may facilitate the development of therapeutics for AF.

/pdf/multi-ethnic-genome-wide-association-study-for-atrial-4uxlzmgkrc.pdf

Multi-Ethnic Genome-wide Association Study for Atrial Fibrillation

Atrial fibrillation (AF) is the most common sustained heart rhythm disorder and is associated with substantial morbidity and mortality. Current treatment options for AF have significant limitations. Basic research has provided information on mechanisms relevant to the management of AF and promises to contribute significantly to future advances, yet many important translational challenges remain. Here, we analyze the therapeutic limitations for which improvement is needed, consider the translational opportunities presented by recent scientific and technological developments, and attempt to look into the future of where these may lead. We first review the limitations of current AF management, with a focus on rhythm control therapy. These include arrhythmia complications, progression to advanced treatment-resistant forms, insufficient effectiveness of available therapeutic options, adverse consequences of therapy, and difficulties in new therapeutic development. The translational challenges in addressing these shortcomings are then addressed, including (1) defining actionable patient-specific arrhythmia mechanisms to enable personalized therapy; (2) identifying and treating key dynamic modulators controlling AF initiation and progression; (3) achieving atrial-restricted targeting of specific molecular arrhythmia mechanisms; and (4) clarifying the response of the substrate to interventions. For each of these, we describe the translational goal and the opportunities created by recent advances in cardiac imaging, computational modeling, rhythm monitoring, ablation technology, and preclinical studies in human samples and animal models. Finally, we consider the prospects for future solutions that might appreciably improve our ability to understand and manage the arrhythmia over the years to come.

Translational Challenges in Atrial Fibrillation

https://research.birmingham.ac.uk/portal/files/40809044/THELANCET_D_16_07655R1_1_for_pure_upload_8March17.pdf

The future of atrial fibrillation management: integrated care and stratified therapy

There are major challenges ahead for clinicians treating patients with atrial fibrillation (AF). The population with AF is expected to expand considerably and yet, apart from anticoagulation, therapies used in AF have not been shown to consistently impact on mortality or reduce adverse cardiovascular events. New approaches to AF management, including the use of novel technologies and structured, integrated care, have the potential to enhance clinical phenotyping or result in better treatment selection and stratified therapy. Here, we report the outcomes of the 6th Consensus Conference of the Atrial Fibrillation Network (AFNET) and the European Heart Rhythm Association (EHRA), held at the European Society of Cardiology Heart House in Sophia Antipolis, France, 17-19 January 2017. Sixty-two global specialists in AF and 13 industry partners met to develop innovative solutions based on new approaches to screening and diagnosis, enhancing integration of AF care, developing clinical pathways for treating complex patients, improving stroke prevention strategies, and better patient selection for heart rate and rhythm control. Ultimately, these approaches can lead to better outcomes for patients with AF.

/pdf/integrating-new-approaches-to-atrial-fibrillation-management-2dhpxoyqe6.pdf

Integrating new approaches to atrial fibrillation management: the 6th AFNET/EHRA Consensus Conference

https://research.birmingham.ac.uk/portal/files/32996301/Syeda_et_al_PITX2_Modulates_Atrial_Membrane_American_College_Cardiology.pdf

PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.

Background 
The left atrial posterior wall (LAPW) is potentially an important area for the development and maintenance of atrial fibrillation. We assessed whether there are regional electrical differences throughout the murine left atrial myocardium that could underlie regional differences in arrhythmia susceptibility.


Methods 
We used high-resolution optical mapping and sharp microelectrode recordings to quantify regional differences in electrical activation and repolarisation within the intact, superfused murine left atrium and quantified regional ion channel mRNA expression by Taqman Low Density Array. We also performed selected cellular electrophysiology experiments to validate regional differences in ion channel function.


Results 
Spontaneous ectopic activity was observed during sustained 1Hz pacing in 10/19 intact LA and this was abolished following resection of LAPW (0/19 resected LA, P<0.001). The source of the ectopic activity was the LAPW myocardium, distinct from the pulmonary vein sleeve and LAA, determined by optical mapping. Overall, LAPW action potentials (APs) were ca. 40% longer than the LAA and this region displayed more APD heterogeneity. mRNA expression of Kcna4, Kcnj3 and Kcnj5 was lower in the LAPW myocardium than in the LAA. Cardiomyocytes isolated from the LAPW had decreased Ito and a reduced IKACh current density at both positive and negative test potentials.


Conclusions 
The murine LAPW myocardium has a different electrical phenotype and ion channel mRNA expression profile compared with other regions of the LA, and this is associated with increased ectopic activity. If similar regional electrical differences are present in the human LA, then the LAPW may be a potential future target for treatment of atrial fibrillation.

/pdf/a-regional-reduction-in-ito-and-ikach-in-the-murine-tc2reiwmb2.pdf

A Regional Reduction in Ito and IKACh in the Murine Posterior Left Atrial Myocardium Is Associated with Action Potential Prolongation and Increased Ectopic Activity.

Stefan M. Kuhlmann

Papers

PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.

A Regional Reduction in Ito and IKACh in the Murine Posterior Left Atrial Myocardium Is Associated with Action Potential Prolongation and Increased Ectopic Activity.

Atrial resting membrane potential confers sodium current sensitivity to propafenone, flecainide and dronedarone.