Background—: Little is known about the mechanisms underlying the transition from paroxysmal to persistent atrial fibrillation (AF). In an ovine model of long-standing persistent AF we tested the hypothesis that the rate of electric and structural remodeling, assessed by dominant frequency (DF) changes, determines the time at which AF becomes persistent. Methods and Results—: Self-sustained AF was induced by atrial tachypacing. Seven sheep were euthanized 11.5±2.3 days after the transition to persistent AF and without reversal to sinus rhythm; 7 sheep were euthanized after 341.3±16.7 days of long-standing persistent AF. Seven sham-operated animals were in sinus rhythm for 1 year. DF was monitored continuously in each group. Real-time polymerase chain reaction, Western blotting, patch clamping, and histological analyses were used to determine the changes in functional ion channel expression and structural remodeling. Atrial dilatation, mitral valve regurgitation, myocyte hypertrophy, and atrial fibrosis occurred progressively and became statistically significant after the transition to persistent AF, with no evidence for left ventricular dysfunction. DF increased progressively during the paroxysmal-to-persistent AF transition and stabilized when AF became persistent. Importantly, the rate of DF increase correlated strongly with the time to persistent AF. Significant action potential duration abbreviation, secondary to functional ion channel protein expression changes (Ca _V 1.2, Na _V 1.5, and K _V 4.2 decrease; Kir2.3 increase), was already present at the transition and persisted for 1 year of follow up. Conclusions—: In the sheep model of long-standing persistent AF, the rate of DF increase predicts the time at which AF stabilizes and becomes persistent, reflecting changes in action potential duration and densities of sodium, L-type calcium, and inward rectifier currents.

Aims: Recent trial data demonstrate beneficial effects of active rhythm management in patients with atrial fibrillation (AF) and support the concept that a low arrhythmia burden is associated with a low risk of AF-related complications. The aim of this document is to summarize the key outcomes of the 9th AFNET/EHRA Consensus Conference of the Atrial Fibrillation NETwork (AFNET) and the European Heart Rhythm Association (EHRA). Methods and results: Eighty-three international experts met in Münster for 2 days in September 2023. Key findings are as follows: (i) Active rhythm management should be part of the default initial treatment for all suitable patients with AF. (ii) Patients with device-detected AF have a low burden of AF and a low risk of stroke. Anticoagulation prevents some strokes and also increases major but non-lethal bleeding. (iii) More research is needed to improve stroke risk prediction in patients with AF, especially in those with a low AF burden. Biomolecules, genetics, and imaging can support this. (iv) The presence of AF should trigger systematic workup and comprehensive treatment of concomitant cardiovascular conditions. (v) Machine learning algorithms have been used to improve detection or likely development of AF. Cooperation between clinicians and data scientists is needed to leverage the potential of data science applications for patients with AF. Conclusions: Patients with AF and a low arrhythmia burden have a lower risk of stroke and other cardiovascular events than those with a high arrhythmia burden. Combining active rhythm control, anticoagulation, rate control, and therapy of concomitant cardiovascular conditions can improve the lives of patients with AF.

Atrial fibrillation is a highly prevalent cardiac arrhythmia and the most important cause of embolic stroke. Although genetic studies have identified an increasing assembly of AF-related genes, the impact of these genetic discoveries is yet to be realized. In addition, despite more than a century of research and speculation, the molecular and cellular mechanisms underlying AF have not been established, and therapy for AF, particularly persistent AF, remains suboptimal. Current antiarrhythmic drugs are associated with a significant rate of adverse events, particularly proarrhythmia, which may explain why many highly symptomatic AF patients are not receiving any rhythm control therapy. This review focuses on recent advances in AF research, including its epidemiology, genetics, and pathophysiological mechanisms. We then discuss the status of antiarrhythmic drug therapy for AF today, reviewing molecular mechanisms, and the possible clinical use of some of the new atrial-selective antifibrillatory agents, as well as drugs that target atrial remodeling, inflammation and fibrosis, which are being tested as upstream therapies to prevent AF perpetuation. Altogether, the objective is to highlight the magnitude and endemic dimension of AF, which requires a significant effort to develop new and effective antiarrhythmic drugs, but also improve AF prevention and treatment of risk factors that are associated with AF complications.

Background—: Dominant frequencies (DFs) of activation are higher in the atria of patients with persistent than paroxysmal atrial fibrillation (AF), and left atrial (LA)-to-right atrial (RA) DF gradients have been identified in both. However, whether such gradients are maintained as long-term persistent AF is established remains unexplored. We aimed at determining in vivo the time course in atrial DF values from paroxysmal to persistent AF in sheep and testing the hypothesis that an LA-to-RA DF difference is associated with LA drivers in persistent AF. Methods and Results—: AF was induced using RA tachypacing (n=8). Electrograms were obtained weekly from an RA lead and an implantable loop recorder implanted near the LA. DFs were determined for 5-second-long electrograms (QRST subtracted) during AF in vivo and in ex vivo optical mapping. Underlying structural changes were compared with weight-matched controls (n=4). After the first AF episode, DF increased gradually during a 2-week period (7±0.21 to 9.92±0.31 Hz; n=6; P <0.05). During 9 to 24 weeks of AF, the DF values on the implantable loop recorder were higher than the RA (10.6±0.08 versus 9.3±0.1 Hz, respectively; n=7; P <0.0001). Subsequent optical mapping confirmed a DF gradient from posterior LA-to-RA (9.1±1.0 to 6.9±0.9 Hz; P <0.05) and demonstrated patterns of activation compatible with drifting rotors in the posterior LA. Persistent AF sheep showed significant enlargement of the posterior LA compared with controls. Conclusions—: In the sheep, transition from paroxysmal to persistent AF shows continuous LA-to-RA DF gradients in vivo together with enlargement of the posterior LA, which harbors the highest frequency domains and patterns of activation compatible with drifting rotors.

Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disorder for which no cure exists. The disease is characterized by premature aging and inevitable death in adolescence due to cardiovascular complications. Most HGPS patients carry a heterozygous de novo LMNA c.1824C > T mutation, which provokes the expression of a dominant-negative mutant protein called progerin. Therapies proven effective in HGPS-like mouse models have yielded only modest benefit in HGPS clinical trials. To overcome the gap between HGPS mouse models and patients, we have generated by CRISPR-Cas9 gene editing the first large animal model for HGPS, a knockin heterozygous LMNA c.1824C > T Yucatan minipig. Like HGPS patients, HGPS minipigs endogenously co-express progerin and normal lamin A/C, and exhibit severe growth retardation, lipodystrophy, skin and bone alterations, cardiovascular disease, and die around puberty. Remarkably, the HGPS minipigs recapitulate critical cardiovascular alterations seen in patients, such as left ventricular diastolic dysfunction, altered cardiac electrical activity, and loss of vascular smooth muscle cells. Our analysis also revealed reduced myocardial perfusion due to microvascular damage and myocardial interstitial fibrosis, previously undescribed readouts potentially useful for monitoring disease progression in patients. The HGPS minipigs provide an appropriate preclinical model in which to test human-size interventional devices and optimize candidate therapies before advancing to clinical trials, thus accelerating the development of effective applications for HGPS patients.