Something abnormal is occurring that results in electrical stimuli being initiated either in the heart and/or perhaps the pulmonary veins, all this leading to afib. What is/are the mechanisms for this abnormality? We know the chemical structures for antiarrythmic medications. How do they operate on a molecular level? Need to look both deep inside the affected cells and also on a more systemic level. Structure yields function.

The mechanisms of AF are likely to vary between patients, depending on factors such as genetic determinants, cardiovascular risk factors, and concomitant heart disease.

• Ca2+-dependent triggered activity seems to underlie atrial ectopy in AF, and has complex underlying molecular mechanisms that increase both cellular Ca2+ load and the leakiness of the sarcoplasmic reticulum Ca2+-release channel (ryanodine receptor)
• Molecular mechanisms promoting re‑entrant activity in patients with AF includeionic properties (such as larger left atrial inward-rectifier background current)and structural properties (such as atrial fibrosis)

Analysis of gene variants associated with AF can provide additional insights into basic mechanisms

(channel subunit mutations, usually accompanied by clear evidence of markedly accelerated repolarization in terms of short QT syndrome, have been described as the probable cause of AF; the involved genes and related K+-currents are KCNJ2, KCNE1, and KCNH2;

given that increased K+ current abbreviates refractoriness and promotes re-entry, while tending to reduce automaticity, these cases of AF are likely to be caused by re-entry).

Zhang et al. reported a family with a mutation in nuclear pore complex protein (nucleoporin) Nup155, which presented with AF and sudden death in early childhood. Ablation of Nup155 in mice resulted in abbreviated ERP and action potential duration, and spontaneous

development of AF probably mediated by re-entry. Several other reports suggest that abnormal automaticity can be central to the pathophysiology of AF. Kazemian et al. described a patient with catecholaminergic polymorphic ventricular tachycardia owing to a ryanodine receptor (RyR2) mutation, who presented with self-terminating AF paroxysms with exercise that were subsequently controlled by β-adrenergic blockade. A loss-of-function junctophilin mutation was identified in a patient with juvenile-onset AF, and found

to enhance RyR2 Ca2+ leak, DADs, and AF in a mouse model. Investigators in another study noted downregulation of the RyR2-targeting microRNA (miR)-106b-25 cluster in AF. Ablation of miR-106b-25 in mice increased RyR2 protein expression and Ca2+ leak, and caused atrial premature complexes and AF inducibility in vivo that were suppressed by an RyR2-stabilizing drug (K201, also known as JTV519)

The molecular determinants of re-entry susceptibility in patients with AF are less well studied than those of spontaneous ectopy. Indices of classical electrical remodelling, such as shortening of APD, are absent in right atrial tissue of patients with AF. In multicellular preparations of right atrial appendages, upstroke velocity, amplitude, duration at 20%, 50%, and 90% of repolarization of action potential, and resting membrane potential were similar in sinus rhythm and patients with AF, and were similarly unchanged in right atrial cardiomyocytes from patients with AF. Preliminary data point to increased small-conductance Ca2+-dependent K+ -current in patients with AF.

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That was a most interesting document. Thank you for sharing. An electrophysiologist who I know seems to feel that the problem may well be intractable. While elucidation of the exact underlying mechanism(s) may be difficult, I think it's certainly possible. My current research, as a retired volunteer, involves microbial ecology. I do, however, have a personal interest in a fib and will use the document as a source for furthering my knowledge.

Thanks, Andrei. I'll be pursuing the references.