Atrial fibrillation risk loci interact to modulate Ca2+-dependent atrial rhythm homeostasis
We report that Tbx5 and Gata4 interact with opposite signs for atrial rhythm controls compared with cardiac development. Using mouse genetics, we found that AF pathophysiology caused by Tbx5 haploinsufficiency, including atrial arrhythmia susceptibility, prolonged action potential duration, and ectopic cardiomyocyte depolarizations, were all rescued by Gata4 haploinsufficiency. In contrast, Nkx2-5 haploinsufficiency showed no combinatorial effect. The molecular basis of the TBX5/GATA4 interaction included normalization of intra-cardiomyocyte calcium flux and expression of calcium channel genes Atp2a2 and Ryr2. Furthermore, GATA4 and TBX5 showed antagonistic interactions on an Ryr2 enhancer. Atrial rhythm instability caused by Tbx5 haploinsufficiency was rescued by a decreased dose of phospholamban, a sarco/endoplasmic reticulum Ca2+-ATPase inhibitor, consistent with a role for decreased sarcoplasmic reticulum calcium flux in Tbx5-dependent AF susceptibility. This work defines a link between Tbx5 dose, sarcoplasmic reticulum calcium flux, and AF propensity. The unexpected interactions between Tbx5 and Gata4 in atrial rhythm control suggest that evaluating specific interactions between genetic risk loci will be necessary for ascertaining personalized risk from genetic association data.
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Conditions: Cardiac Arrhythmias; Atrial Fibrillation Intervention: Device: a wearable adhesive cardiac monitoring device Sponsors: St. Michael's Hospital, Toronto; Southlake Regional Health Centre; University Health Network, Toronto Recruiting
ConclusionsIf our hypothesis is confirmed, the utility of the MedDiet enriched with EVOO in slowing the progression of AF will be proven, preventing recurrences and potentially reducing complications.ClinicalTrials.gov IdentifierNCT03053843
iRhythm and Verily announced a partnership last month to “co-develop solutions intended to provide early warning, diagnosis and management for patients, particularly for those with silent or undiagnosed AF.” We spoke with iRhythm CEO Kevi...
Authors: Liu L, Zhang H, Mao H, Li X, Hu Y Abstract MicroRNAs (miRNAs) play a key role in various pathological processes like atrial fibrillation (AF), which is a common cardiac arrhythmia. Exosomes are essential information carrier in the intercellular communication. Therefore, this study aimed to investigate the effects of exosomal miR-320d on cardiomyocytes with AF and related mechanisms. To do this, AMSCs were transfected with miR-320d mimics, AMSCs-derived exosomes were co-cultured with cardiomyocytes with AF. MTT, TUNEL staining, flow cytometry, real-time PCR, western blots, and luciferase reporter assays wer...
Conclusion We here describe the PREDICT AF trial design, which will enable the discovery of biomarkers that truly predict POAF and new-onset atrial fibrillation by combining tissue and plasma-derived biomarkers with comprehensive clinical follow-up data. Trial registration Retrospectively registered NCT03130985 27 April 2017.