Atrial fibrillation (AF) is commonly observed in patients with hypertension and is associated with pathologically elevated cardiomyocyte stretch. AF triggers have been linked to subcellular Ca2+ abnormalities, while their association with stretch remains elusive. Caveolae are mechanosensitive membrane structures, that play a role in both Ca2+ and cyclic adenosine monophosphate (cAMP) signaling. Therefore, caveolae could provide a mechanistic connection between cardiomyocyte stretch, Ca2+ mishandling, and AF. In isolated mouse atrial myocytes, cell stretch was mimicked by hypotonic swelling, which increased cell width (by ∼30%, p<0.05), but not cell length. Swelling induced a temporal rise (1-5 min) in Ca2+ transient (CaT) amplitude and spontaneous Ca2+ sparks frequency (CaSpF). Electron microscopy analysis revealed a 2-fold decrease in caveolae density in stretched cells. Alternatively, disruption of caveolae via (1) 10 mM methyl-β-cyclodextrin (MβCD) or (2) genetic knockout of caveolin-3 augmented both CaT and CaSpF, similar to swelling. Immunofluorescent analysis revealed the augmentation of protein kinase A (PKA)-phosphorylated ryanodine receptors (at both Ser2030 and Ser2808) in swelled and MβCD-treated cells as compared to isotonic ones (p<0.05). CaSpF in swelled and MβCD-treated cells was reduced to the unstretched level via (1) inhibition of cAMP production by 100 μM SQ22536, or (2) reduction of PKA activity by 1 μM H-89. Transfection of myocytes with either sarcolemma- or cytosol-targeted Epac2-camps FRET sensors revealed a sharp decrease of cAMP signal in the submembrane compartment and a transient rise in the cytosol during the stretch. Atrial myocytes from pressure-overloaded hearts (4-weeks transaortic constriction) showed 1.6 times higher CaSpF than wild-type cells (p<0.01), which was significantly reduced after incubation with SQ22536 (p<0.05). Our findings demonstrate that short-time cell swelling augments Ca2+ handling in atrial myocytes via caveolae/cAMP/PKA mechano-chemical signal transduction, which could contribute to atrial arrhythmogenesis under pathological conditions.