Armand R.J. Girbes

Renal Function, Neurohormonal Activation, and Survival in Patients With Chronic Heart Failure

BACKGROUND Because renal function is affected by chronic heart failure (CHF) and it relates to both cardiovascular and hemodynamic properties, it should have additional prognostic value. We studied whether renal function is a predictor for mortality in advanced CHF, and we assessed its relative contribution compared with other established risk factors. In addition, we studied the relation between renal function and neurohormonal activation. METHODS AND RESULTS The study population consisted of 1906 patients with CHF who were enrolled in a recent survival trial (Second Prospective Randomized study of Ibopamine on Mortality and Efficacy). In a subgroup of 372 patients, plasma neurohormones were determined. The baseline glomerular filtration rate (GFR(c)) was calculated using the Cockroft Gault equation. GFR(c) was the most powerful predictor of mortality; it was followed by New York Heart Association functional class and the use of angiotensin-converting enzyme inhibitors. Patients in the lowest quartile of GFR(c) values (<44 mL/min) had almost 3 times the risk of mortality (relative risk, 2. 85; P<0.001) of patients in the highest quartile (>76 mL/min). Impaired left ventricular ejection fraction (LVEF) was only modestly predictive (P=0.053). GFR(c) was inversely related with N-terminal atrial natriuretic peptide (ANP; r=-0.53) and, to a lesser extent, with ANP itself (r=-0.35; both P<0.001). CONCLUSIONS Impaired renal function (GFR(c)) is a stronger predictor of mortality than impaired cardiac function (LVEF and New York Heart Association class) in advanced CHF, and it is associated with increased levels of N-terminal ANP. Moreover, impaired renal function was not related to LVEF, which suggests that factors other than reduced cardiac output are causally involved.

Electrophysiologic profile of ibopamine in patients with congestive heart failure and ventricular tachycardia and relation to its effects on hemodynamics and plasma catecholamines

Programmed electrical stimulation was performed in 12 patients with moderate to severe congestive heart failure and ventricular tachycardia (VT) to study possible arrhythmogenic properties of ibopamine, a new orally active dopamine agonist. Ibopamine induced no significant changes in spontaneous cycle length, PR, QRS, QTc, AH or HV intervals, and also right ventricular effective refractory periods were unaffected (for paced cycle lengths of 600 and 430 ms, respectively, using 1 extrastimulus: 287 +/- 16 ms at baseline vs 283 +/- 27 ms after ibopamine and 270 +/- 23 ms during the control study vs 262 +/- 19 ms after ibopamine). In 6 of the 8 patients with coronary artery disease but in none of the 4 patients with dilated cardiomyopathy, sustained VT was induced before and after ibopamine. Proarrhythmia was present in 1 patient, who became inducible after ibopamine. However, 1 patient had sustained VT only at baseline but not after ibopamine. The number of extrastimuli required for VT induction was equal (2.7 +/- 0.2 vs 2.7 +/- 0.2). Holter monitoring showed no changes in ventricular premature complexes, ventricular couplets and runs of VT after 1 week of ibopamine therapy. The signal-averaged electrocardiogram was abnormal in 11 and showed late potentials in 5 patients, but no changes occurred after ibopamine. During hemodynamic evaluation, increases in cardiac (32%) and stroke volume (34%) indexes were seen after administration of 100 mg of ibopamine, accompanied by a decrease in vascular resistance and filling pressures. Plasma norepinephrine decreased significantly after ibopamine (p = 0.02) but plasma epinephrine was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

EFFECTS OF DOPAMINERGIC AGENTS ON CARDIAC AND RENAL-FUNCTION IN NORMAL MAN AND IN PATIENTS WITH CONGESTIVE-HEART-FAILURE

Dopamine is an effective drug in the management of acute congestive heart failure. Its beneficial action is due to both cardiovascular--peripheral vasodilation and positive inotropy--and renal effects. Dopexamine is one of the newer dopamine agonists. Like dopamine, however, it can only be administered intravenously, and its value in the chronic treatment of congestive heart failure is limited. For this reason, dopamine analogs were developed with oral bioavailability, including levodopa, fenoldopam and biopamine. Although both levodopa and fenoldopam have shown beneficial hemodynamic effects, these agents cannot be recommended for general use in patients with congestive heart failure. Levodopa frequently causes side effects, especially nausea, and fenoldopam induces an increase in neurohumoral activity, which limits its long-term efficacy. Ibopamine has vasodilatory, mild inotropic and diuretic properties and it lowers plasma norepinephrine levels. Since ibopamine is usually well tolerated, it appears to have the most interesting profile of these oral dopaminergic agents.

Clinical and autonomic effects of ibopamine as adjunct to angiotensin-converting enzyme inhibitors in chronic heart Failure

BACKGROUND The purpose of this study was to determine the additive value of ibopamine in heart failure patients who are treated with angiotensin-converting enzyme inhibitors. Ibopamine exerts hemodynamic and neurohumoral effects, and is beneficial in mild heart failure; however, its additive value in more advanced disease in unclear. METHODS AND RESULTS The study was a stand-alone, double-blind, randomized parallel group comparison of ibopamine (100 mg 3 times daily) and placebo in 59 patients with New York Heart Association functional class III-IV heart failure. Patients were clinically stable on drug treatment, including an angiotensin-converting enzyme inhibitor, and they were randomized to ibopamine (n = 29) or placebo (n = 30). Assessments were performed at baseline and after 3 months of treatment, and included measurement of peak oxygen consumption, plasma neurohormones, ambulatory arrhythmias, and heart rate variability. At baseline, the two groups were well matched, including age (mean, 63 years), left ventricular ejection fraction (0.23), and peak oxygen consumption (15.4 mL/min/kg). After 3 months, four patients had dropped out of the study because of progressive heart failure (ibopamine, n = 1; placebo, n = 3; not significant) and two because of side effects (n = 1/1). Exercise time and peak oxygen consumption were not significantly affected (exercise time: ibopamine, +54 [95% confidence interval, -12, 120] seconds; placebo, +19 [-42, 81] seconds; peak oxygen consumption: ibopamine, +0.3 [-0.5, 1,2] mL/min/kg; placebo, +0.2 [-0.7, 1.0] mL/min/kg). Plasma neurohormones and ventricular arrhythmias during ambulatory monitoring were also unaffected. In contrast, heart rate variability parameters, in particular those associated with vagal tone (rMMSD, high-frequency power), significantly increased after 3 months on ibopamine (P = .01 vs placebo). CONCLUSIONS In this group of patients with clinically stable moderate to severe chronic heart failure, only a marginal and statistically nonsignificant effect on clinical parameters was observed after 3 months of treatment with ibopamine. Heart rate variability parameters, however, were significantly affected by ibopamine, despite the absence of an effect on plasma neurohormones.

Effects of ibopamine on the increase in plasma norepinephrine levels during exercise in congestive heart failure

Congestive heart failure (CHF) is accompanied by increased levels of plasma norepinephrine (PNE) at rest. During exercise, PNE levels increase rapidly in patients with CHF,1 causing skeletal vasoconstriction and muscle underperfusion. Because long-term sympathetic activation may be detrimental in patients with CHF,2 inhibition of this sympathetic drive would appear to be beneficial. The oral dopamine agonist ibopamine causes vasodilation and reduces PNE levels at rest in patients with CHF.3 However, the influence of ibopamine on peak oxygen consumption (VO2) and PNE levels during exercise in patients with CHF is unknown, and was investigated in this study.

Oral Ibopamine Substitution in Patients with Intravenous Dopamine Dependence

In a prospective open study we evaluated whether intravenous dopamine infusions can be safely switched to enterally administered ibopamine in dopamine-dependent patients. Six patients defined as being clinically stable, normovolaemic, but dopamine dependent, i.e. with repeated inability to stop intravenous dopamine, were included. Ibopamine was administered via a nasogastric or nasoduodenal tube. During the initial 48-hour period of ibopamine administration the dopamine infusion was gradually decreased and then discontinued. Arterial blood pressure was continuously recorded via a 20-gauge cannula in the radial artery. Urine output was measured each hour. In all 6 patients it was possible to decrease and then discontinue the dopamine infusion whilst maintaining haemodynamic stability and an appropriate diuresis. It was then possible to discharge the patients from the intensive care unit. Normovolaemic, clinically stable but dopamine-dependent patients may be weaned off intravenous dopamine by substitution of enterally administered ibopamine, allowing discharge from the intensive care unit.