Steven R. Goldsmith

Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure

Abstract Resting hemodynamic measurements and plasma levels of catecholamines and renin activity were studied in 55 hospitalized treated patients with congestive heart failure in clinically stable condition. Plasma norepinephrine (mean ± standard error of the mean 594 ± 51 pg/ml, range 153 to 1,868) and plasma renin activity (mean 12.9 ± 2.4 ng/ml per hr, range 0.6 to 85.2) values were significantly (probability [p] It is concluded that patients with congestive heart failure can be categorized on the basis of neurohumoral activity. The statistically significant correlations between plasma norepinephrine and hemodynamic evidence of cardiac dysfunction suggest that the sympathetic response is either a marker of or a contributor to the hemodynamic derangement. Because hemodynamic abnormalities did not correlate with plasma renin activity despite a statistically significant correlation between plasma norepinephrine and plasma renin activity, it appears that the two systems are independently activated in congestive heart failure but that sympathetic stimulation may be one factor contributing to renin release. Further studies are needed to assess the usefulness of plasma hormone levels in evaluating and treating patients with congestive heart failure.

The Neurohumoral Axis in Congestive Heart Failure

The incidence of congestive heart failure is increasing in the United States. This common syndrome is characterized not only by impaired ventricular function but also by an increase in some endogenous vasoconstrictor substances, including norepinephrine, angiotensin II, and arginine vasopressin. Although activation of the systems that release these substances is presumed to be compensatory (to maintain perfusion pressure during inadequate flow), the sympathetic nervous system, renin-angiotensin-aldosterone system, and arginine vasopressin may contribute to the pathogenesis of the syndrome. The excessive vasoconstriction present in heart failure likely produces a further burden on the failing myocardium. New strategies in therapy are being developed to counteract the activation of vasoconstrictor forces in congestive heart failure. Data indicate that selective blockade of the renin-angiotensin system is useful. Preliminary data suggest that inhibition of the sympathetic nervous system may be helpful, and inhibition of vasopressin in animals with heart failure is being studied. New and more selective therapy for heart failure may come from these studies.

Acute Vasoconstrictor Response to Intravenous Furosemide in Patients with Chronic Congestive Heart Failure: Activation of the Neurohumoral Axis

Hemodynamic and neurohumoral responses to acute diuretic therapy were measured in 15 patients with severe chronic heart failure given intravenous furosemide, 1.3 +/- 0.6 (SD) mg/kg body weight. Left ventricular pump function deteriorated by 20 minutes, as indicated by a fall in stroke volume index (27 +/- 8 to 24 +/- 7 mL/min X m2 body surface area, p less than 0.01) and an increase in left ventricular filling pressure (28 +/- 7 to 33 +/- 9 mm Hg, p less than 0.01). Increases occurred in heart rate (87 +/- 13 to 91 +/- 16 beats/min, p less than 0.01), mean arterial pressure (90 +/- 15 to 96 +/- 15 mm Hg, p less than 0.01), systemic vascular resistance (1454 +/- 394 to 1676 +/- 415 dynes X s X cm-5, p less than 0.01), plasma renin activity (9.9 +/- 8.5 to 17.8 +/- 16 ng/mL X h, p less than 0.05), plasma norepinephrine level (667 +/- 390 to 839 +/- 368 pg/mL, p less than 0.01), and plasma arginine vasopressin level (6.2 +/- 1.3 to 8.3 +/- 2.0 pg/mL, p less than 0.01). During the next 3.5 hours the patients had diuresis (2085 +/- 1035 mL) and the expected fall in filling pressure (28 +/- 7 to 22 +/- 10 mm Hg, p less than 0.01). Neurohumoral indicators also returned toward the control levels. Intravenous furosemide, in patients with severe chronic heart failure, is associated with acute pump dysfunction temporally related to activation of the neurohumoral axis.

Ultrafiltration in Decompensated Heart Failure with Cardiorenal Syndrome

BACKGROUND Ultrafiltration is an alternative strategy to diuretic therapy for the treatment of patients with acute decompensated heart failure. Little is known about the efficacy and safety of ultrafiltration in patients with acute decompensated heart failure complicated by persistent congestion and worsened renal function. METHODS We randomly assigned a total of 188 patients with acute decompensated heart failure, worsened renal function, and persistent congestion to a strategy of stepped pharmacologic therapy (94 patients) or ultrafiltration (94 patients). The primary end point was the bivariate change from baseline in the serum creatinine level and body weight, as assessed 96 hours after random assignment. Patients were followed for 60 days. RESULTS Ultrafiltration was inferior to pharmacologic therapy with respect to the bivariate end point of the change in the serum creatinine level and body weight 96 hours after enrollment (P=0.003), owing primarily to an increase in the creatinine level in the ultrafiltration group. At 96 hours, the mean change in the creatinine level was -0.04±0.53 mg per deciliter (-3.5±46.9 μmol per liter) in the pharmacologic-therapy group, as compared with +0.23±0.70 mg per deciliter (20.3±61.9 μmol per liter) in the ultrafiltration group (P=0.003). There was no significant difference in weight loss 96 hours after enrollment between patients in the pharmacologic-therapy group and those in the ultrafiltration group (a loss of 5.5±5.1 kg [12.1±11.3 lb] and 5.7±3.9 kg [12.6±8.5 lb], respectively; P=0.58). A higher percentage of patients in the ultrafiltration group than in the pharmacologic-therapy group had a serious adverse event (72% vs. 57%, P=0.03). CONCLUSIONS In a randomized trial involving patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion, the use of a stepped pharmacologic-therapy algorithm was superior to a strategy of ultrafiltration for the preservation of renal function at 96 hours, with a similar amount of weight loss with the two approaches. Ultrafiltration was associated with a higher rate of adverse events. (Funded by the National Heart, Lung, and Blood Institute; ClinicalTrials.gov number, NCT00608491.).

Increased plasma arginine vasopressin levels in patients with congestive heart failure.

The antidiuretic hormone arginine vasopressin could contribute to both the vasoconstriction and impaired water handling frequently found in patients with congestive heart failure. In order to determine basal levels for vasopressin in this condition, plasma vasopressin was measured by radioimmunoassay in a group of 31 patients with advanced congestive heart failure. At the same time, plasma norepinephrine, plasma renin activity and numerous hemodynamic variables were also measured. In a subgroup of patients, the response of vasopressin to hemodynamic changes induced by nitroprusside infusion and to inhibition of the renin-angiotensin system with captopril was studied. The basal vasopressin levels in the patients were compared with those obtained from 51 comparably aged normal subjects. The mean vasopressin level (± standard error of the mean) in the patients was 9.5 ± 0.89 pg/ml as compared with 4.7 ± 0.66 (probability [p] Thus, vasopressin levels measured under steady state conditions are usuallv increased in patients with congestive heart failure. The increase is not dependent on reduced cardiac index. There appears to be an abnormality in the relation between vasopressin and serum sodium in some persons and vasopressin does not respond to acute hemodynamic changes with or without the inhibition of the renin-angiotensin system. The mechanisms causing increased vasopressin levels and their biologic importance in congestive heart failure remain to be defined.

Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial

IMPORTANCE Small studies suggest that low-dose dopamine or low-dose nesiritide may enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction; however, neither strategy has been rigorously tested. OBJECTIVE To test the 2 independent hypotheses that, compared with placebo, addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy will enhance decongestion and preserve renal function in patients with acute heart failure and renal dysfunction. DESIGN, SETTING, AND PARTICIPANTS Multicenter, double-blind, placebo-controlled clinical trial (Renal Optimization Strategies Evaluation [ROSE]) of 360 hospitalized patients with acute heart failure and renal dysfunction (estimated glomerular filtration rate of 15-60 mL/min/1.73 m2), randomized within 24 hours of admission. Enrollment occurred from September 2010 to March 2013 across 26 sites in North America. INTERVENTIONS Participants were randomized in an open, 1:1 allocation ratio to the dopamine or nesiritide strategy. Within each strategy, participants were randomized in a double-blind, 2:1 ratio to active treatment or placebo. The dopamine (n = 122) and nesiritide (n = 119) groups were independently compared with the pooled placebo group (n = 119). MAIN OUTCOMES AND MEASURES Coprimary end points included 72-hour cumulative urine volume (decongestion end point) and the change in serum cystatin C from enrollment to 72 hours (renal function end point). RESULTS Compared with placebo, low-dose dopamine had no significant effect on 72-hour cumulative urine volume (dopamine, 8524 mL; 95% CI, 7917-9131 vs placebo, 8296 mL; 95% CI, 7762-8830 ; difference, 229 mL; 95% CI, -714 to 1171 mL; P = .59) or on the change in cystatin C level (dopamine, 0.12 mg/L; 95% CI, 0.06-0.18 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, 0.01; 95% CI, -0.08 to 0.10; P = .72). Similarly, low-dose nesiritide had no significant effect on 72-hour cumulative urine volume (nesiritide, 8574 mL; 95% CI, 8014-9134 vs placebo, 8296 mL; 95% CI, 7762-8830; difference, 279 mL; 95% CI, -618 to 1176 mL; P = .49) or on the change in cystatin C level (nesiritide, 0.07 mg/L; 95% CI, 0.01-0.13 vs placebo, 0.11 mg/L; 95% CI, 0.06-0.16; difference, -0.04; 95% CI, -0.13 to 0.05; P = .36). Compared with placebo, there was no effect of low-dose dopamine or nesiritide on secondary end points reflective of decongestion, renal function, or clinical outcomes. CONCLUSION AND RELEVANCE In participants with acute heart failure and renal dysfunction, neither low-dose dopamine nor low-dose nesiritide enhanced decongestion or improved renal function when added to diuretic therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01132846.

Relationship of exercise capacity to resting left ventricular performance and basal plasma norepinephrine levels in patients with congestive heart failure

Seventeen patients with chronic congestive heart failure (CHF) were studied to assess the relationship of resting left ventricular function, as measured by noninvasive and invasive methods, to maximal exercise capacity, as measured by peak total body oxygen consumption (VO2). Supine basal plasma norepinephrine (NE) was also measured to evaluate its relationship to the severity of heart failure and to determine whether it may be a better predictor of exercise capacity in patients with CHF than the more commonly employed noninvasive and invasive tests of left ventricular function. Fourteen of the 17 patients underwent upright bicycle exercise (average peak VO2 10.60 +/- 1.40 ml/kg/min, +/- SEM) to their symptomatic maximum. There was no significant correlation between peak VO2 and the noninvasive measurements of left ventricular performance obtained at rest, including cardiothoracic ratio, left ventricular internal dimension by M-mode echo, percent shortening of the minor axis by M-mode echo, and radionuclide ejection fraction. Hemodynamic measurements were performed in 16 patients. The hemodynamic measurements at rest also failed to correlate with exercise capacity. The supine basal plasma NE, which was elevated in these 17 patients (612 +/- 100 pg/ml), had an inverse relationship with stroke work index (r - -0.70, p less than 0.01) and stroke index (r = -0.83, p less than 0.001) and a positive correlation with right atrial pressure (r = 0.81, p less than 0.001). Although both noninvasive and invasive measurements at rest failed to correlate significantly with peak VO2 during exercise, the plasma NE had a significant inverse correlation with peak exercise VO2 (r = -0.50, p less than 0.05). The basal supine plasma NE is therefore elevated in patients with CHF, is a marker for the severity of CHF as measured by hemodynamics performed at rest, and is a better predictor of exercise capacity than standard noninvasive and invasive tests performed at rest.

Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure

The activity of the sympathetic nervous system is increased at rest in patients with congestive heart failure. To determine whether this augmentation is carried over during dynamic upright exercise, 14 patients with congestive heart failure were stressed maximally during upright bicycle ergometry. Plasma norepinephrine and epinephrine levels were measured in the basal upright (sitting) posture before and during maximal exercise. The results were compared with those in six healthy control subjects before and during maximal exercise. Plasma norepinephrine increased during exercise from a mean (+/- standard error of the mean) of 650 +/- 95 to 1,721 +/- pg/ml in the group with heart failure. This increase was significantly less (p less than 0.001) than that in the control group (from 318 +/- 36 to 3,230 +/- 418 pg/ml). However, for equivalent levels of total body oxygen consumption (VO2), the group with heart failure had higher levels of plasma norepinephrine than the control group. Plasma epinephrine was similar in the two groups in the basal upright position (92 +/- 18 and 92 +/- 26 pg/ml), but it increased more during exercise in the normal subjects (743 +/- 210 pg/ml) than in the group with heart failure (167 +/- 67 pg/ml) (p less than 0.001). The percent increase in norepinephrine correlated with the percent change in VO2 in the group with heart failure (r = 0.62, p less than 0.02), but the percent change in epinephrine did not. There is, therefore, a disturbance in the sympathetic nervous system during exercise in patients with congestive heart failure. Although norepinephrine increases in such patients to a greater extent than in normal subjects at lower levels of exercise, the extremely high levels of norepinephrine and epinephrine generated by normal subjects during maximal upright exercise do not occur in patients with heart failure.

Neurohumoral control mechanisms in congestive heart failure

Neurohumoral vasoconstrictor systems may play an important role in the hemodynamic derangement and natural history of congestive heart failure (CHF) by raising impedance to left ventricular ejection and shifting blood centrally to augment cardiac filling. Activation of the sympathetic nervous system, and renin-angiotensin system, and the antidiuretic hormone-vasopressin system can be demonstrated in clinical CHF by increased plasma levels of norepinephrine, renin activity, and arginine vasopressin. Because the magnitude of increase in each of these hormones varies widely from patient to patient, profiling of the neurohumoral response might provide new insight into the mechanisms of regulation of the circulation in CHF and into specific management with drugs to inhibit or reverse the vasoconstrictor process. Preliminary encouraging experience with converting-enzyme inhibitors to block formation of angiotensin II and alpha-receptor blockers to inhibit norepinephrine-induced vasoconstriction raise the possibility that selective therapy may eventually have a place in long-term management of CHF. Controlled trials in a larger patient population are now required.

Contrasting immediate and long-term effects of isosorbide dinitrate on exercise capacity in congestive heart failure.

Abstract Exercise duration and maximal oxygen uptake in patients with heart failure are not suddenly increased after the administration of hemodynamically effective doses of a vasodilator, but they are increased after long-term treatment with these drugs. To explore these differing responses, we had 16 patients with chronic left ventricular failure perform exercise to symptomatic maximum before and 90 minutes after the oral administration of a single 40 mg dose of isosorbide dinitrate. Exercise was then repeated after three months of randomly assigned double-blind long-term treatment with isosorbide dinitrate (eight patients) or placebo (eight patients). Maximal oxygen consumption at control averaged 12.9 ± 1.8 ml/kg/min in the group subsequently assigned to isosorbide dinitrate, and 13.9 ± 1.7 ml/kg/min in the group given the placebo. After the first dose of nitrate, maximal oxygen consumption was unchanged in either group. After three months of nitrate treatment, maximal oxygen consumption increased by 58 percent to 19.4 ± 3.1 ml/kg/min (p