Alternans of the atrial posterior wall pulmonary vein junction as a driver for atrial fibrillation and a target for pharmacological therapy
M Lin, A Whitley, A Swiderska, J Burke, A Trafford, K DibbAbstract
Introduction and Aims
Atrial fibrillation (AF), the commonest arrhythmia, often occurs in the setting of heart failure (HF). AF frequently originates from atrial posterior wall pulmonary vein junction (PVJ). In patients AF initiation has been linked with cardiac alternans which is beat to beat variation in the size or shape of the electrical signal. We have shown in a sheep model of HF that alternans often precede AF, however, whether alternans arise preferentially at the PVJ is unknown. Tadalafil (TAD), a phosphodiesterase-5 inhibitor, has antiarrhythmic effects, but its ability to suppress alternans has not been investigated. Therefore, we aimed to investigate if there is regional heterogeneity in the susceptibility to alternans and if tadalafil can inhibit alternans in healthy and HF sheep.
Methods
HF was induced in sheep by tachypacing the right ventricle via an implanted pacemaker. The left atrium was removed from the healthy and failing hearts of female Welsh Mountain sheep (aged 12-24 months) and loaded with the Ca2+ and voltage indicators Rhod-2AM and RH237 respectively. Optical mapping was used to simultaneously visualize endocardial action potential (AP) and Ca2+ transients during specific pacing protocols. PVJ, free wall (FW), left atrial appendage (LAA) and the whole atria were selected for analysis. OMapScope 5.9.4 and custom written software were used for alternans analysis.
Results
Cardiac alternans tended to occur at longer diastolic intervals at the PVJ (threshold in control PVJ: 361.8±61.51ms, FW: 214.5±36.44ms, LAA: 214.5±38.86ms, n=11, p=0.0363; threshold in HF PVJ: 650±119ms, FW: 322.5±87.6ms, LAA: 400±40.82ms, n=4; p=0.0869). The magnitude of alternans was greater at PVJ in both control and HF (control: p=0.0087, n=11; HF: p=0.0031, n=4). Alternans of AP emerged at longer diastolic intervals than calcium alternans, indicating the primary driver of tissue level alternans was voltage (control: AP alternans threshold 325.5±53.18ms, calcium alternans threshold 215.5±43.03ms, n=11, p=0.0156; HF: AP alternans threshold 650±119ms, calcium alternans threshold 297.5±73.07ms, n=4, p=0.0433). Tadalafil (50nM) protected the atrium from alternans by decreasing the cycle length at which alternans first occurred in HF (baseline 650±119ms, acute TAD 295±125.2ms, n=4, p=0.0278) and by decreasing the alternans magnitude in the PVJ in both control and HF groups (control: p=0.0061, n=6; HF: p=0.005, n=4).
Conclusion
In both healthy and HF sheep, the pulmonary vein junction is more susceptible to cardiac alternans with greater magnitude. Acute tadalafil treatment can suppress the susceptibility and magnitude of alternans which we expect will limit the transition of alternans to AF and represents a potential antiarrhythmic strategy in HF.alternans threshold and magnitudethe effect of acute tadalafil treatment