PLASMA NOREPINEPHRINE, PLASMA-RENIN ACTIVITY, AND CONGESTIVE-HEART-FAILURE - RELATIONS TO SURVIVAL AND THE EFFECTS OF THERAPY IN V-HEFT-II

Background. Congestive heart failure is a clinical syndrome characteri zed by neuroendocrine activation. Measurements of plasma norepinephrin e and plasma renin activity were performed in the Vasodilator-Heart Fa ilure Trial II (V-HeFT II) to characterize the effects of therapy on n euroendocrine activation and to examine the responses to therapy among patients with different degrees of activation. Methods and Results. T he baseline median plasma norepinephrine value (n=743) was 490 pg/mL a nd the baseline median plasma renin activity (n=737) was 6.9 ng - mL-1 . hr-1. Baseline plasma renin activity and plasma norepinephrine corr elated poorly with each other (r=0.12), implying that these two neuroe ndocrine systems are being activated by separate processes. By univari ate analysis, the logarithms of the plasma norepinephrine (p<0.0001) a nd the plasma renin activity (p=0.01) were significantly related to al l-cause mortality. In a multivariate analysis that included other sign ificant univariate prognostic variables (i.e., baseline ejection fract ion, peak oxygen consumption during exercise, and cardiothoracic ratio ), log plasma norepinephrine but not plasma renin activity remained a significant (p=0.02) predictor of mortality. Baseline plasma norepinep hrine correlated poorly with baseline left ventricular ejection fracti on (r= -0.18), peak oxygen consumption (r=-0.15), and cardiothoracic r atio (r=0.11). Neither the plasma norepinephrine (r=0.09) nor the plas ma renin activity (r=0.18) was closely associated with a quality of li fe assessment at baseline. The baseline plasma norepinephrine level in patients randomized to enalapril (mean, 593+/-388 [SD] pg/mL; n=372) and to hydralazine and isosorbide dinitrate (mean, 544+/-297 pg/mL, n= 371) were similar. Thirteen weeks after randomization, plasma norepine phrine did not change (-5+/-393 pg/mL) in 312 patients randomized to e nalapril but increased significantly by 74+/-311 pg/mL (p<0.0001) in 3 00 patients assigned to hydralazine-isosorbide dinitrate. The plasma n orepinephrine increased significantly more in patients assigned to hyd ralazine-isosorbide dinitrate than those on enalapril at both 13 weeks (p=0.01) and at 1 year (p=0.04) (90+/-302 pg/mL [n=2401 versus 14+/-3 76 pg/mL [n=265]). Based on previous reports and examination of surviv al among several plasma norepinephrine strata, the baseline plasma nor epinephrine data were grouped into three relatively homogeneous strata for further analysis. The cumulative mortality was significantly diff erent between the three strata (p<0.0001). The patients with plasma no repinephrine >900 pg/mL had a higher mortality than those with corresp onding values from 601 to 900 pg/mL or <600 pg/mL. The survival benefi t of enalapril compared with hydralazine-isosorbide dinitrate was most evident in those patients with a plasma norepinephrine value >900 pg/ mL. Although the plasma renin activity was not strongly associated wit h survival, patients in the upper quartile (>16 ng . mL-1 . hr-1) had the worst prognosis. Among this group, the patients on enalapril demon strated significantly better survival than those on hydralazine-isosor bide dinitrate (p=0.02). Conclusions. This study confirms that plasma norepinephrine is an independent predictor of prognosis in patients wi th congestive heart failure. Hydralazine-isosorbide dinitrate treatmen t, unlike enalapril treatment, was associated with increased plasma no repinephrine concentration during the first year of follow-up. The ena lapril group had a significantly lower mortality, and this survival be nefit of enalapril as compared with hydralazine-isosorbide dinitrate w as most evident among patients with the most marked neuroendocrine act ivation. Neuroendocrine activation is an important prognostic factor f or patients with congestive heart failure and is an important determin ant of the differential response to vasodilators.