Intracoronary infusion of dobutamine to patients with and without severe congestive heart failure. Dose-response relationships, correlation with circulating catecholamines, and effect of phosphodiesterase inhibition.

We infused dobutamine into the left main coronary artery of 24 patients with severe congestive heart failure (CHF) and 8 normal subjects without hemodynamic dysfunction. The maximal +dP/dt response to intracoronary (IC) dobutamine in CHF patients was only 37% of that in normals. This decrease in maximal response was not associated with a rightshift in the EC50 for dobutamine's effect on +dP/dt, or a decrease in the affinity of myocardial beta adrenergic receptors for dobutamine determined in vitro. In nine of the CHF patients, IC dobutamine infusion was followed by IC infusion of the phosphodiesterase inhibitor milrinone, and subsequently, by a second IC infusion of dobutamine. After IC milrinone, the increase in +dP/dt caused by IC dobutamine (74 +/- 10%) was significantly greater than that caused by the first infusion of dobutamine (52 +/- 11%; P less than 0.003) or milrinone (42 +/- 6%; P less than 0.001). Resting plasma norepinephrine was markedly elevated in CHF patients (837 +/- 208 ng/liter), but not in normal subjects (142 +/- 32 ng/liter); and the increase in +dP/dt caused by IC dobutamine was inversely related to resting plasma norepinephrine levels (r = -0.653; P less than 0.001). IC dobutamine caused a dose-related decrease in plasma norepinephrine (maximal effect, -160 +/- 31 ng/liter; P less than 0.001). Thus, (a) the maximal inotropic response to dobutamine is markedly depressed in patients with severe CHF, and is significantly greater after pretreatment with the phosphodiesterase inhibitor milrinone; (b) the impairment in inotropic response to dobutamine is inversely related to circulating norepinephrine levels; and (c) myocardial stimulation by dobutamine results in withdrawal of sympathetic tone.

Effect of bolus milrinone on hemodynamic variables and pulmonary vascular resistance in patients with severe left ventricular dysfunction: a rapid test for reversibility of pulmonary hypertension.

OBJECTIVES: To examine the feasibility of using milrinone to test pulmonary vascular reactivity in patients before heart transplantation, we tested the hypothesis that milrinone would lower pulmonary vascular resistance (PVR) in patients with severe heart failure. BACKGROUND: Fixed pulmonary hypertension is a risk factor for right heart failure and death after orthotopic heart transplantation. Sodium nitroprusside, the agent used most commonly to test for reversibility of pulmonary hypertension before transplantation, requires dose titration and is frequently limited by hypotension. Milrinone is an intravenously active phosphodiesterase inhibitor that acts rapidly and exerts both positive inotropic and direct vasodilator effects in patients with heart failure. The ability of milrinone to lower PVR in patients with heart failure has not been tested. METHODS: In 27 patients with New York Heart Association functional class III or IV heart failure referred for heart transplantation with a PVR > or = 200 dynes-s-cm-5, we measured the hemodynamic response to a single intravenous bolus of milrinone (50 micrograms/kg body weight) infused over 1 min. RESULTS: Milrinone decreased PVR in all patients. The effect was maximal 5 to 10 min after the bolus and persisted for at least 20 min. The reduction in PVR at 5 min ([mean +/- SEM] 31 +/- 4%) was associated with a 42 +/- 4% increase in cardiac output and decreases of 12 +/- 4% and 16 +/- 5% in mean pulmonary artery and pulmonary artery wedge pressures, respectively, but no change in transpulmonary pressure gradient. Milrinone had no effect on heart rate or systemic arterial pressure. The magnitude of the decrease in PVR correlated inversely with the milrinone-induced increase in cardiac output. CONCLUSIONS: Bolus milrinone consistently decreases PVR in patients with pulmonary hypertension secondary to severe heart failure. This effect is rapid in onset and well tolerated, even by patients with low systemic arterial pressure. An intravenous bolus of milrinone can be used to test for the reversibility of pulmonary hypertension in patients with heart failure undergoing evaluation for heart transplantation.

Survival of patients with severe congestive heart failure treated with oral milrinone.

The safety and efficacy of long-term oral milrinone therapy were evaluated over a 2 1/2 year period in 100 patients who had severe congestive heart failure despite conventional therapy. Long-term oral milrinone therapy (27 +/- 8 mg/day initial dose) was well tolerated; drug-related side effects occurred in only 11% of patients and led to drug withdrawal in only 4% of patients. Of 94 patients evaluated after 1 month of therapy, 51% had improved by at least one New York Heart Association functional class. Despite hemodynamic and clinical improvements, life table analysis showed a 39% mortality rate at 6 months and a 63% mortality rate at 1 year of therapy. Characteristics at study entry that predicted death within 6 months included more advanced functional class, impaired renal function, lower right ventricular ejection fraction, presence of nonsustained ventricular tachycardia on 24 hour ambulatory electrocardiography, more impaired baseline hemodynamic function and absence of clinical improvement after 1 month of milrinone therapy. Multivariate analysis selected lower baseline cardiac index and aortic systolic pressure as the most significant variables in predicting death; patients who died of progressive heart failure had less frequent use of antiarrhythmic drugs and greater increases in furosemide and milrinone doses during long-term follow-up than did those who died suddenly. Thus, although milrinone is well tolerated and produces early symptomatic benefits in approximately half of patients with congestive heart failure refractory to conventional therapy, there is no evidence that it improves the high baseline mortality in this disorder.

Mechanism of the attenuated peak heart rate response to exercise after orthotopic cardiac transplantation.

The mechanism responsible for attenuation of the peak heart rate response to exercise in patients after cardiac transplantation was studied. Because the donor heart is believed to be surgically denervated, the peak heart rate response to exercise is dependent primarily on 1) an increase in the circulating levels of the catecholamines norepinephrine and epinephrine at peak exercise, and 2) the end-organ responsiveness of the sinoatrial (SA) node to beta-adrenergic stimulation. To assess the former mechanism, the levels of plasma nonepinephrine and epinephrine were measured at rest and at peak exercise on a cycle ergometer in 23 transplant recipients an average of 7 +/- 1 months after transplantation and in 23 normal subjects matched for age. To assess the latter mechanism, the heart rate response to a graded infusion of isoproterenol was determined in six normal subjects with and without atropine pretreatment and in eight transplant recipients. In transplant recipients, both the absolute plasma levels of nonepinephrine and epinephrine at peak exercise and the increments from baseline to peak exercise were comparable with or greater than those in normal subjects. In transplant recipients, the isoproterenol dose that increased heart rate by 25 beats/min over baseline was not different from that in atropine-treated normal subjects (normal subjects 9 +/- 2 ng/kg per min; transplant recipients 11 +/- 1 ng/kg per min; p = NS). These data show that after cardiac transplantation, there is a normal or slight elevation of circulating catecholamines at peak exercise, and that the responsiveness of the SA node to beta-adrenergic stimulation is normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of milrinone on complex ventricular arrhythmias in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy.

To determine whether oral milrinone therapy has an effect on complex ventricular arrhythmias in patients with severe congestive heart failure and, if so, whether a change in the severity of complex ventricular arrhythmias after 1 week of milrinone therapy is associated with a change in the mode or frequency of cardiac mortality, a retrospective analysis was performed to determine the frequency of ventricular tachycardia and the density of ventricular couplets on 24-hour ambulatory electrocardiographic recordings performed before and 1 week after initiation of oral milrinone therapy in 74 consecutive patients with New York Heart Association functional class III or IV congestive heart failure. The endpoints of mortality and mode of death were assessed during a mean follow-up of 6 months. In 91% of the patients, 1 week of oral milrinone therapy was associated with no significant change (85%) or a significant decrease (6%) in the density of ventricular couplets and frequency of ventricular tachycardia. However, in 9% of patients the frequency of complex ventricular arrhythmias increased significantly at the end of 1 week of oral milrinone therapy. In this subgroup, neither total cardiac mortality nor the incidence of sudden cardiac death was significantly higher than that in patients with no change or a decrease in complex ventricular ectopic activity.

Effects of intracoronary acetylcholine and atropine on basal and dobutamine-stimulated left ventricular contractility.

BACKGROUND: The role of cholinergic pathways in modulating left ventricular contractile function in humans is not known. This study evaluated the effect of a cholinergic agonist (acetylcholine) and antagonist (atropine) on basal and beta-adrenergically stimulated left ventricular contractile function in normal subjects and subjects with denervated hearts after cardiac transplantation. METHODS AND RESULTS: Six subjects with normal left ventricular function and seven subjects who were 1 to 3 years after cardiac transplantation were studied. Acetylcholine, atropine, and the beta-adrenergic agonist dobutamine were infused via the left main coronary artery, and changes in left ventricular contractile function were assessed by measurement of peak +dP/dt. Intracoronary dobutamine increased +dP/dt by 70 +/- 15% and 66 +/- 20% in the normal subjects and transplant recipients, respectively. Intracoronary acetylcholine and atropine alone each had no effect on left ventricular +dP/dt in either normal subjects or transplant recipients. The concurrent infusion of acetylcholine with dobutamine reduced the response to dobutamine by 66 +/- 10% and 79 +/- 9% in normal subjects and transplant recipients, respectively. The concurrent infusion of atropine with dobutamine potentiated the response to dobutamine by 25 +/- 7% in normal subjects but had no effect in transplant recipients. CONCLUSIONS: Stimulation and inhibition of cholinergic receptors in the human heart can modulate the positive inotropic response to beta-adrenergic stimulation.

Beta-adrenergic inotropic responsiveness of patients with heart failure: studies with intracoronary dobutamine infusion.

Although there is theoretical and indirect evidence to suggest that patients with severe congestive heart failure may have desensitization of myocardial beta-adrenergic responsiveness, there is little direct evidence in patients. The purpose of this study was to determine whether myocardial beta-adrenergic inotropic responsiveness is reduced in patients with severe congestive heart failure and markedly elevated plasma norepinephrine levels. To assess myocardial beta-adrenergic inotropic responsiveness, the beta-adrenergic agonist dobutamine was infused directly into the left main coronary artery, and the change in +dP/dt was measured as an index of change in inotropic state. Eight patients with severe New York Heart Association functional Class III and IV congestive heart failure were compared with 4 patients without significant congestive heart failure. The increase in +dP/dt at an intracoronary dobutamine infusion rate of 25 micrograms/min in patients with severe congestive heart failure was significantly less than in the patients without heart failure (heart failure, 33 +/- 8%; no heart failure, 69 +/- 12%; p less than 0.05). Although the maximum intracoronary dobutamine infusion rate was substantially higher in patients with heart failure (94 +/- 25 micrograms/min) compared with patients without heart failure (38 +/- 7 micrograms/min), the increase in +dP/dt at maximum infusion rates was also significantly less in patients with heart failure (heart failure, 52 +/- 8%; no heart failure, 93 +/- 24%; p less than 0.05). Plasma norepinephrine concentration was normal in the 4 patients without heart failure and was markedly elevated (range, 307-3,967 ng/l) in the patients with severe heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of myocardial alpha 1-adrenergic receptor stimulation and blockade on contractility in humans.

BACKGROUND: Although alpha-adrenergic receptors are present in both normal and failing human left ventricular myocardium and mediate a positive inotropic effect in several other species, it is not known whether stimulation of myocardial alpha-adrenergic receptors exerts a positive inotropic effect or contributes to basal contractile state in vivo in humans. METHODS AND RESULTS: We studied 15 patients with angiographically normal coronary arteries (seven with normal left ventricular function and eight with left ventricular failure). To avoid the confounding effects of changes in ventricular loading conditions and systemic reflex mechanisms, the alpha-adrenergic receptor-selective antagonist phentolamine and agonist phenylephrine were infused directly into the left main coronary artery, and the change in contractile state was assessed by measuring left ventricular peak (+)dP/dt. Phentolamine alone had no effect on left ventricular contractility. Phenylephrine exerted a concentration-related positive inotropic effect in patients with normal as well as those with failing ventricles. The alpha-adrenergic effect of phenylephrine, defined as the component blocked by phentolamine, was significantly less in patients with ventricular failure (108 +/- 28 mm Hg/sec) than in normal subjects (248 +/- 54 mm Hg/sec; p less than 0.03). CONCLUSIONS: Myocardial alpha-adrenergic receptors do not contribute to the maintenance of basal left ventricular contractile state in humans. However, stimulation of myocardial alpha-adrenergic receptors exerts a positive inotropic effect, the magnitude of which may be attenuated in patients with heart failure.

Impaired chronotropic response to exercise in patients with congestive heart failure. Role of postsynaptic beta-adrenergic desensitization.

The mechanism responsible for the attenuated heart rate (HR) response to exercise in patients with congestive heart failure (CHF) was investigated in 46 normal subjects and 59 patients with CHF stratified by peak exercise oxygen consumption (VO2). The peak exercise HR and the increment in HR from rest to peak exercise were decreased in CHF patients, and both correlated strongly with peak VO2 (r = 0.810, p less than 0.0001; r = 0.863, p less than 0.0001, respectively). Peak exercise norepinephrine level (NE) and the increment in NE from rest to peak exercise were not attenuated in CHF patients. Resting NE was elevated in CHF patients and correlated inversely with peak VO2 (r = -0.595, p less than 0.001). However, no significant correlation occurred between peak VO2 and either peak exercise NE or the exercise increment in NE. The ratio of the exercise increments in HR and NE, and indirect index of sinoatrial node sympathetic responsiveness, was markedly reduced in CHF patients and was inversely related to the severity of exercise impairment. Likewise, the HR response to a graded isoproterenol infusion was markedly reduced in CHF patients. Age-matching of normal subjects and CHF patients did not affect the foregoing observations. Infusion of CHF patients with the phosphodiesterase inhibitor milrinone caused a significant increase in the ratio of the exercise increments in HR and NE. These data strongly suggest that the attenuated HR response to exercise in CHF patients is due, at least in part, to postsynaptic desensitization of the beta-adrenergic receptor pathway.