In heart failure (HF) , sympathetic nerve activity is increased. Measurements in HF patients of cardiac norepinephrine spillover, reflecting cardiac sympathetic nerve activity (CSNA), indicate that it is increased earlier and to a greater extent than sympathetic activity to other organs. This has important consequences because it worsens prognosis, provoking arrhythmias and sudden death. To elucidate the mechanisms responsible for the activation of CSNA in HF, we made simultaneous direct neural recordings of CSNA and renal SNA (RSNA) in two groups of conscious sheep: normal animals and animals in HF induced by chronic, rapid ventricular pacing. In normal animals, the level of activity, measured as burst incidence (bursts of pulse related activity/100 heart beats), was significantly lower for CSNA (30 ؎ 5%) than for RSNA (94 ؎ 2%). Furthermore, the resting level of CSNA, relative to its maximum achieved while baroreceptors were unloaded by reducing arterial pressure, was set at a much lower percentage than RSNA. In HF, burst incidence of CSNA increased from 30 to 91%, whereas burst incidence of RSNA remained unaltered at 95%. The sensitivity of the control of both CSNA and RSNA by the arterial baroreflex remained unchanged in HF. These data show that, in the normal state, the resting level of CSNA is set at a lower level than RSNA, but in HF, the resting levels of SNA to both organs are close to their maxima. This finding provides an explanation for the preferential increase in cardiac norepinephrine spillover observed in HF.arterial baroreflex ͉ renal sympathetic nerve activity ͉ sheep H eart failure (HF) is associated with an increase in sympathetic nerve activity (SNA) that shows a large regional heterogeneity in the extent to which activity increases. The level of SNA to different organs may be estimated by measurements of regional norepinephrine (NE) spillover, and it has been observed that in HF there is a greater increase in NE spillover from the heart than the kidney, and no change from the gut (1, 2). This increase in cardiac NE spillover occurs at an earlier stage of HF than it does to other organs (3, 4), again suggesting a preferential stimulation of cardiac SNA (CSNA) in HF. The increase in CSNA in HF is detrimental as it can promote the progression of the disease and leads to development of arrhythmias and sudden death (5). The mechanisms accounting for the increase in CSNA in HF are poorly understood.One explanation for the preferential increase in cardiac NE spillover in HF is that, in the normal state, the resting levels of CSNA and renal SNA (RSNA) are similar, but in HF, sympathetic activity increases more to the heart than to the kidney. An alternative explanation is that the resting level of CSNA is set at a lower level compared with that to other organs, such the kidney, and in HF, both CSNA and RSNA increase to near maximum levels. Both explanations seem plausible, but the resting levels of CSNA and RSNA have not been simultaneously recorded in the normal state and compared with activities ...