Sympathetic function in cardiac disorders.Upon cardio-renal sympathetic activity and effects of nitroglycerin in human heart failure

Abstract: This study explores pathophysiological mechanisms and prognostic implications of sympathetic activation in patients with atherosclerotic renovascular hypertension (RVH) and with chronic heart failure (CHF). Hitherto, it is unknown whether cardiac sympathetic activation is present in patients with RVH, the presence of which could relate to the increased cardiovascular mortality observed in this disorder. During nitroglycerin (GTN) infusion, baroreflex control of renal sympathetic activity and GTN biotransformation were studied in patients with CHF and healthy subjects (HS). Furthermore, the relative importance of renal function, sympathetic activation and other established prognostic indicators on outcome, were tested in a well characterised cohort of patients with CHF. Isotope dilution with measurements of systemic and regional noradrenaline (NA) spillover was used to assess cardiac and systemic sympathetic activity in patients with RVH, CHF and in healthy subjects (HS). In patients with CHF, also renal NA spillover was assessed. Long-term outcome in terms of the combined end-point of all-cause mortality and heart transplantation was assessed in patients with CHF in relation to regional NA spillover rates and established risk factors for adverse prognosis. Cardiac, but not systemic, NA spillover was increased in patients with RVH as compared to HS. Renal NA spillover above group median value in patients with CHF was associated with a three-fold increase in the relative risk for all-cause mortality or heart transplantation independent of age, diagnosis, left ventricular systolic function, cardiac index, renal function and renal blood flow. Cardiopulmonary baroreceptor unloading with GTN, the low dose GTN level, resulted in an increased systemic NA spillover in HS but not in patients with CHF. To decrease arterial blood pressures, a tenfold higher GTN infusion rate was needed in the CHF group vs. HS at the high dose GTN level, which resulted in ten-fold higher GTN concentration in CHF vs. HS. The high dose GTN level resulted in decreased renal NA spillover in patients with CHF, while no change was observed in HS. The relative concentration of the GTN metabolite 1,2-GDN was lower in CHF vs. HS. Furthermore, the ratio of 1,2-GDN to 1,3-GDN showed a negative correlation to the plasma GTN levels in CHF patients. Cardiac sympathetic activity was increased in patients with RVH, which adds to the risk imposed by left ventricular hypertrophy and atherosclerotic disease. Renal sympathetic activity and renal dysfunction seem to carry similar negative prognostic information in patients with CHF, although only increased renal NA spillover was independently associated with an increased risk for all-cause mortality or heart transplantation in the present study. Nitroglycerin infusion associated with both arterial and cardiopulmonary pressure reductions and improved peripheral perfusion, resulted in reduced renal NA spillover in CHF patients. Patients with CHF showed an impaired hemodynamic response to GTN versus HS and our findings suggest that differences in GTN biotransformation, related to the heart failure syndrome contribute to the reduced GTN sensitivity. The present findings underline the importance of identifying and target renal abnormalities, by reducing blood pressure and by treatment with beta-adrenergic receptor blockade.