Localized Pulmonary Vein Scar Promotes Atrial Fibrillation in High Left Atrial Pressure.

BACKGROUND: Pulmonary vein (PV) ablation is unsuccessful in atrial fibrillation (AF) patients with high left atrial (LA) pressure. Increased atrial stretch by increased pressure is proarrhythmic for AF, and myocardial scar alters wall deformation. We hypothesized that localized PV scar is proarrhythmic for AF in high LA pressure. METHODS: Radiofrequency energy was delivered locally in the right PV of healthy sheep. The sheep recovered for 4 months. Explanted hearts (n = 9 PV scar, n = 9 controls) were perfused with 1:4 blood:Tyrode's solution in a four-chamber working heart setup. Programmed PV stimulation was performed during low (∼12 mmHg) and high (∼25 mmHg) LA pressure. An AF inducibility index was calculated based on the number of induction attempts and the number of attempts causing AF (run of ≥ 20 premature atrial complexes). RESULTS: In high LA pressure, the presence of PV scar increased the AF inducibility index compared with control hearts (0.83 ± 0.20 vs. 0.38 ± 0.40 arb. unit, respectively, p = 0.014). The diastolic stimulation threshold in high LA pressure was higher (108 ± 23 vs. 77 ± 16 mA, respectively, p = 0.006), and its heterogeneity was increased in hearts with PV scar compared with controls. In high LA pressure, the refractory period was shorter in PV scar than in control hearts (178 ± 39 vs. 235 ± 48 ms, p = 0.011). CONCLUSION: Localized PV scar only in combination with increased LA pressure facilitated the inducibility of AF. This was associated with changes in tissue excitability remote from the PV scar. Localized PV ablation is potentially proarrhythmic in patients with increased LA pressure.

Manifestations of gene expression profiles in human right atrial myocardium caused by mechanical stretch.

This investigation was aimed to identify gene profiles in human atrial myocardium in response to chronic mechanical stretch. Right atrial appendages from 21 patients were divided into 2 groups based on the size of right atrial volume. The microarray DATA analyses differentially identified 335 genes (> 2.0-fold, corrected P < 0.05) including "functionally unknown genes". This study identified 26 up-regulated genes (natriuretic peptide B, G protein subunit gamma 13, thyroid stimulating hormone beta, etc.) and 23 down-regulated genes (oligodendrocyte transcription factor 1, carbonic anhydrase 12, etc.), which could be responsible for chronic stretch-mediated structural remodeling in the atrium.

Would right atrial stretch inhibit sodium intake following GABAA receptor activation in the lateral parabrachial nucleus?

The knowledge of the mechanisms underlying circulating volume control may be achieved by stretching a balloon placed at the junction of the superior vena cava-right atrial junction (SVC-RAJ). We investigated whether the inflation of a balloon at the SVC-RAJ inhibits the intake of 0.3M NaCl induced by GABAA receptor activation in the lateral parabrachial nucleus (LPBN) in euhydrated and satiated rats. Male Wistar rats (280-300 g) with bilateral stainless steel LPBN cannulae and balloons implanted at the SVC-RAJ were used. Bilateral injections of the GABAA receptor agonist muscimol (0.5 ηmol/0.2l) in the LPBN with deflated balloons increased intake of 0.3M NaCl (30.1 ± 3.9 vs. saline: 2.2 ± 0.7)ml/210 min, n=8) and water (17.7 ± 1.9 vs. saline: 2.9 ± 0.5 ml/210 min). Conversely, 0.3M NaCl (27.8 ± 2.1 ml/210 min) and water (22.8 ± 2.3 ml/210 min) intake were not affected in rats with inflated balloons at the SVC-RAJ. The results show that sodium and water intake induced by muscimol injected into the LPBN was not affected by balloon inflation at the SVC-RAJ. We suggest that the blockade of LPBN neuronal activity with muscimol injections impairs inhibitory mechanisms activated by signals from cardiopulmonary volume receptors determined by balloon inflation.

Antiarrhythmic effect of ranolazine in combination with class III drugs in an experimental whole-heart model of atrial fibrillation.

BACKGROUND: Ranolazine is evaluated for antiarrhythmic therapy of atrial fibrillation (AF). The electrophysiologic mechanisms of ranolazine in combination with class III drugs were studied in an isolated whole-heart model of stretch-related AF. METHODS AND RESULTS: Thirty rabbits were fed with amiodarone (50 mg/kg/day, n = 10), dronedarone (50 mg/kg/day, n = 10), or placebo (n = 10) for 6 weeks. Subsequently, in isolated hearts, AF was induced by high-rate atrial pacing and acute atrial dilatation. In placebo-treated hearts, d,l-sotalol (50 µM) was acutely administered. Ranolazine (10 µM) was additionally infused in all groups. Chronic amiodarone (+26 ± 7 ms, P < 0.05) or dronedarone (+22 ± 4 ms, P < 0.05) as well as acute application of d,l-sotalol (+20 ± 3 ms, P < 0.05) increased atrial action potential duration (aAPD90 ). Additional treatment with ranolazine did not significantly change aAPD90 (P = ns). Class III drugs did not affect interatrial conduction time, while ranolazine significantly increased it (amiodarone group: +15 ± 3 ms, dronedarone group: +11 ± 3 ms, sotalol group: +15 ± 6 ms; P < 0.05 each). Ranolazine led to an additional increase in atrial effective refractory period (aERP), thus leading to an enhanced atrial postrepolarization refractoriness (aPRR, +17 ± 6 ms, +21 ± 4 ms and +16 ± 8 ms, P < 0.05, respectively). Acute atrial dilatation increased AF incidence compared with baseline. Amiodarone-pretreated hearts showed a lower incidence of AF. Additional infusion of ranolazine further diminished AF. Dronedarone or acute infusion of sotalol did not significantly suppress AF, while additional treatment with ranolazine in these groups also reduced AF incidence. CONCLUSION: In this study, ranolazine on top of class III antiarrhythmic therapy had a beneficial effect. The increase in interatrial conduction time and marked atrial aPRR suppressed AF. These results shed further light on a potential therapeutic benefit of ranolazine on top of conventional antiarrhythmic therapy for rhythm control in AF.