Abstract—The hypothesis that cellular hypertrophy in congestive heart failure (CHF) modulates mechanosensitive (ie, swelling- or stretch-activated) channels was tested. Digital video microscopy and amphotericin–perforated-patch voltage clamp were used to measure cell volume and ion currents in ventricular myocytes isolated from normal dogs and dogs with rapid ventricular pacing–induced CHF. In normal myocytes, osmotic swelling in 0.9× to 0.6× isosmotic solution (296 mOsm/L) was required to elicit an inwardly rectifying swelling-activated cation current (ICir,swell) that reversed near –60 mV and was inhibited by 10 μmol/L Gd3+, a mechanosensitive channel blocker. Block ofICir,swellby Gd3+simultaneously reduced the volume of normal cells in hyposmotic solutions by up to ≈10%, but Gd3+had no effect on volume in isosmotic solution. In contrast,ICir,swellwas persistently activated under isosmotic conditions in CHF myocytes, and Gd3+decreased cell volume by ≈8%. Osmotic shrinkage in 1.1× to 1.5× isosmotic solution inhibited bothICir,swelland Gd3+-induced cell shrinkage in CHF cells, whereas osmotic swelling only slightly increasedICir,swell. TheK0.5and Hill coefficient for Gd3+block ofICir,swelland Gd3+-induced cell shrinkage were estimated as ≈2.0 μmol/L and ≈1.9, respectively, for both normal and CHF cells. In both groups, the effects of Gd3+on current and volume were blocked by replacing bath Na+and K+and were linearly related with varying Gd3+concentration and the degree of cell swelling. CHF thus altered the set point for and caused persistent activation ofICir,swell. This current may contribute to dysrhythmias, hypertrophy, and altered contractile function in CHF and may be a novel target for therapy.