Atrial remodeling is observed in hypertensive heart disease and also in atrial fibrillation (AF). It often disturbs Ca2+ homeostasis, which could contribute to arrhythmogenesis. Common strategies to reduce cardiac remodeling in heart failure have failed to improve the prognosis of AF in large clinical trials, indicating different underlying mechanisms of remodeling. In this study, we investigate if Ca2+ handling responds differently to rapid atrial pacing and hypertension as triggers of atrial remodeling. In 11 anaesthetized, landrace pigs (1 vol% isoflurane, 25 μg/kg/h fentanyl), a custom-made, telemetry-controlled pacemaker was implanted. Rapid atrial pacing (600 bpm) for 6 w induced sustained AF (no detectable SR for > 1h). A group of 8 pigs received a subcutaneous DOCA-depot (100 mg/kg, 90-day release) and a high-lipid/salt diet during 12 w, to induce hypertension (HYP). The left atrial area was assessed by echocardiography during sedation (20 mg/kg ketamine, 0.5 mg/kg midazolam, 0.5 mg/kg azaperone) repetitively. Values of 41 untreated pigs (19-70 kg) served as controls to consider natural growth. In 11 landrace pigs, rapid atrial pacing (600 bpm) for 6 w induced sustained AF (no detectable SR for > 1h). A group of 8 pigs received a subcutaneous DOCA-depot and a high-lipid/salt diet during 12 w, to induce hypertension (HYP). The left atrial area was assessed by echocardiography during sedation repetitively. Values obtained in 41 healty, untreated pigs (19-70 kg) served as controls to consider natural growth. Cells were isolated from left (LA) or right atrium (RA)(N=6 AF, N=3 HYP, N=4 control). Calcium transients (CaT) were measured during field stimulation using Fura-2 AM (0.5 – 2 Hz, 37°C). SR Ca2+ content was measured as the peak of caffeine-induced CaT. Western blots were performed on homogenates of 3 RA and 3 LA in each group, and normalized to total protein with Ponceau staining. Data are expressed as mean ± s.e.m. After 2 w of rapid pacing, left atrial size was larger compared to control and further increased after 6 w of pacing (Fig A). In hypertensive pigs, the systolic blood pressure was 139±11 vs 95±6 mmHg after 12 w treatment (P<0.05, tail-cuff-method). The increase in left atrial size was less pronounced (Fig B). In single cells isolated from LA after 6 w pacing, the frequency-dependent Ca2+ response was blunted, and CaT amplitude tended to be decreased (0.55±0.03, n=9, vs 0.64±0.04 F340/380 in control, n=5, 1 Hz), despite higher SR Ca2+ content (1.7±0.15 vs 1.1±0.38 F340/380 in control, n=4, P<0.05, ANOVA). Fractional release was less efficient. At the molecular level, Na/Ca exchanger was upregulated, while PLB phosphorylation levels were decreased; rate of Ca2+ decline was unaltered. Ca2+ handling was not different between LA and RA. In HYP, CaT amplitude was decreased in RA (0.41±0.03F340/F380, n=9), but maintained in LA cells (0.58±0.04 F340/380, n=9). Compared to RA, Ca2+ decline was faster in LA (86±24 ms vs 142±16 ms in RA), which was associated with an increased PLB phosphorylation at Ser16 and Thr17 in LA. SR Ca2+ content was not increased. In conclusion, in hypertensive remodeling, Ca2+ handling is better maintained in LA than RA. In AF, in both LA and RA, the Ca2+ release process is less efficient. Unlike in hypertension, SR Ca2+ load is increased, which heralds a potential risk of Ca2+ overload and arrhythmias.