Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) and pacemakers have been shown to benefit from moderately accelerated pacing rates compared to the standard 60bpm. HFpEF patients often present with prolonged P-wave duration (PWD) and atrial fibrillation. Right atrial appendage pacing (RAAP) lengthens PWD, RA septal (RASP) has a neutral effect, while Bachmann’s bundle pacing (BBP) normalizes or shortens PWD compared to sinus rhythm. The mechanical and hemodynamic effects of atrial pacing site selection remain unknown. Aim To investigate the impact of RAAP, RASP and BBP on cardiac mechanics and hemodynamics in an established cohort of virtual HFpEF patients undergoing accelerated pacing. Method HFpEF with prolonged PWD was simulated using the validated CircAdapt computational model of the human cardiovascular system. First, left ventricular (LV) diastolic dysfunction was simulated by decreasing LV myocardial relaxation rate and compliance, such that mean left atrial (LA) pressure (mLAP) was 15mmHg. Second, PWD was prolonged by prescribing a gradual electrical activation delay from RA to LA of 140ms. We then simulated atrial pacing with three different lead positions (Fig.1, left) and gradually increased pacing rate with a constant 120-ms paced atrioventricular (AV) delay. The CircAdapt model computed regional LA strain and mLAP with RAAP, RASP, and BBP. Cardiac output (5L/min) and mean arterial pressure (92mmHg) were kept constant in all simulations. Results Simulated BBP demonstrated the most synchronous LA mechanical activation and function, characterized by uniform segmental LA strain patterns and highest LA reservoir strain (LASR) (Fig.1, middle, with colored arrows highlighting the mechanical dyssynchrony). Hemodynamically (Fig.1, right), BBP acutely decreased mLAP (-1.0mmHg) at the initial heart rate of 60bpm, while RAAP increased it (+0.3mmHg). As pacing rate accelerated, BBP reduces filling pressure (mLAP: -2.8mmHg), more than RASP (-1.8mmHg) or RAAP (-1.2mmHg) at 80bpm. At high pacing rates, RASP and RAAP adversely increase mLAP, due to the prolonged atrial contraction duration and shorter LV filling time. Conclusion Our simulations of different atrial pacing sites in virtual HFpEF patients suggest that BBP yields the most synchronous LA activation pattern and a more substantial reduction in filling pressures with accelerated atrial pacing compared to RASP. Reduction in mLAP with accelerated pacing was attenuated with RAAP. While our study concentrated on a specific paced AV interval, the favorable outcomes observed with BBP could be further improved by including different, rate-adaptive, AV protocols.Fig 1.