Background The aldosterone inhibitor eplerenone (EPL) has been shown to reduce the incidence of AF in patients with systolic heart failure, but the mechanism is unknown. Objectives We hypothesized that by reducing atrial dilatation and fibrosis in the absence of heart failure EPL also reduces AF burden and prevents AF perpetuation. Methods We conducted a randomized-controlled study in 34 sheep that were atrially tachypaced (13±1 weeks). We compared daily oral EPL (N=19) versus sugar-pill (SP) treatment (N=15) from the start of tachypacing. The endpoint was a continuous 7-day stretch of persistent AF (N=29) or completion of 23-weeks tachypacing (N=5). Results EPL significantly reduced the rate of left atrial dilatation increase during AF progression. Atria from EPL-treated sheep had less smooth muscle actin protein, collagen-III expression, interstitial atrial fibrosis and cell hypertrophy than SP-treated sheep atria. However, EPL did not modify the AF-induced increase in the rate of dominant frequency and ion channel densities seen under SP treatment, but prolonged the time to persistent AF in 26% of animals. It also reduced the degree of fibrillatory conduction, AF inducibility and AF burden. Conclusions In the sheep model, EPL mitigates fibrosis and atrial dilatation, modifies AF inducibility and AF complexity, and prolongs the transition to persistent AF in 26% of animals, but it does not prevent AF-induced electrical remodeling or AF persistence. The results highlight structural remodeling as a central upstream target to reduce AF burden, and the need to prevent electrical remodeling to avert AF perpetuation.

The acetylcholine-activated inward rectifier potassium current ( I) is constitutively active in persistent atrial fibrillation (AF). We tested the hypothesis that the blocking of I with the small molecule chloroquine terminates persistent AF. We used a sheep model of tachypacing-induced, persistent AF, molecular modeling, electrophysiology, and structural biology approaches. The 50% inhibition/inhibitory concentration of I block with chloroquine, measured by patch clamp, was 1 μM. In optical mapping of sheep hearts with persistent AF, 1 μM chloroquine restored sinus rhythm. Molecular modeling suggested that chloroquine blocked the passage of a hydrated potassium ion through the intracellular domain of Kir3.1 (a molecular correlate of I) by interacting with residues D260 and F255, in proximity to I228, Q227, and L299. HN heteronuclear single-quantum correlation of purified Kir3.1 intracellular domain confirmed the modeling results. F255, I228, Q227, and L299 underwent significant chemical-shift perturbations upon drug binding. We then crystallized and solved a 2.5 Å X-ray structure of Kir3.1 with F255A mutation. Modeling of chloroquine binding to the mutant channel suggested that the drug's binding to the pore becomes off centered, reducing its ability to block a hydrated potassium ion. Patch clamp validated the structural and modeling data, where the F255A and D260A mutations significantly reduced I block by chloroquine. With the use of numerical and structural biology approaches, we elucidated the details of how a small molecule could block an ion channel and exert antiarrhythmic effects. Chloroquine binds the I channel at a site formed by specific amino acids in the ion-permeation pathway, leading to decreased I and the subsequent termination of AF.-Takemoto, Y., Slough, D. P., Meinke, G., Katnik, C., Graziano, Z. A., Chidipi, B., Reiser, M., Alhadidy, M. M., Ramirez, R., Salvador-Montañés, O., Ennis, S., Guerrero-Serna, G., Haburcak, M., Diehl, C., Cuevas, J., Jalife, J., Bohm, A., Lin,Y.-S., Noujaim, S. F. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule.

The use of ICE during catheter-based ablation of complex cardiac substrates provides technical features that may decrease complications and increase accuracy while applying radiofrequency, especially in training centers where fellows start to perform complex procedures.

Background Post-COVID-19 patients may incur myocardial involvement secondary to systemic inflammation. Our aim was to detect possible oedema/diffuse fibrosis using cardiac magnetic resonance imaging (CMR) mapping and to study myocardial deformation of the left ventricle (LV) using feature tracking (FT). Methods Prospective analysis of consecutively recruited post-COVID-19 patients undergoing CMR. T1 and T2 mapping sequences were acquired and FT analysis was performed using 2D steady-state free precession cine sequences. Statistical significance was set to p<0.05. Results Included were 57 post-COVID-19 patients and 20 healthy controls, mean age 59±15 years, men 80.7%. The most frequent risk factors were hypertension (33.3%) and dyslipidaemia (36.8%). The contact-to-CMR interval was 81±27 days. LV ejection fraction (LVEF) was 61±10%. Late gadolinium enhancement (LGE) was evident in 26.3% of patients (19.3%, non-ischaemic). T2 mapping values (suggestive of oedema) were higher in the study patients than in the controls (50.9±4.3 ms vs 48±1.9 ms, p<0.01). No between-group differences were observed for native T1 nor for circumferential strain (CS) or radial strain (RS) values (18.6±3.3% vs 19.2±2.1% (p=0.52) and 32.3±8.1% vs 33.6±7.1% (p=0.9), respectively). A sub-group analysis for the contact-to-CMR interval (<8 weeks vs ≥8 weeks) showed that FT-CS (15.6±2.2% vs 18.9±2.6%, p<0.01) and FT-RS (24.9±5.8 vs 33.5±7.2%, p<0.01) values were lower for the shorter interval. Conclusions Post-COVID-19 patients compared to heathy controls had raised T2 values (related to oedema), but similar native T1, FT-CS and FT-RS values. FT-CS and FT-RS values were lower in post-COVID-19 patients undergoing CMR after <8 weeks compared to ≥8 weeks.

NCT01561144; results.