Coronary artery fistula after mitral valve surgery.
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Aged↗
Biomedical subjects
W S Colucci
Publications and source records attributed to W S Colucci.
Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure.
In patients with congestive heart failure, atrial natriuretic factor may serve as a counter-regulatory hormone, offsetting the vasoconstrictive and volume-retentive effects of the sympathetic nervous system, the renin-angiotensin-aldosterone system and vasopressin. Indeed, the plasma levels of atrial natriuretic factor and the vasoconstrictor hormones are often simultaneously elevated in these patients. It is not known, however, whether atrial natriuretic factor remains responsive to sudden reductions in atrial pressure in patients with chronic heart failure, or is unresponsive like the vasoconstrictor systems. To examine this issue, the plasma concentrations of atrial natriuretic factor and the vasoconstrictor hormones were measured in 20 normal subjects and 12 patients with chronic congestive heart failure during incremental lower body negative pressure, an intervention that lowers atrial pressure. In the normal subjects, incremental lower body negative pressure at -10, -20 and -40 mm Hg decreased central venous pressure and pulse pressure. At maximal lower body negative pressure, plasma atrial natriuretic factor levels decreased from 51 +/- 5 to 27 +/- 3 pg/ml (p less than 0.01), whereas increases occurred in plasma levels of norepinephrine (194 +/- 11 to 385 +/- 70 pg/ml, p less than 0.01), renin activity (1.4 +/- 0.2 to 3.9 +/- 0.1 ng/ml per h, p less than 0.01) and vasopressin (1.3 +/- 0.1 to 6.4 +/- 2.4 pg/ml, p less than 0.05). In the patients with congestive heart failure, lower body negative pressure also reduced central venous pressure. Baseline plasma atrial natriuretic factor levels were markedly elevated, averaging 438 +/- 138 pg/ml, and decreased to 317 +/- 87 pg/ml at maximal lower body negative pressure (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Do positive inotropic agents adversely affect the survival of patients with chronic congestive heart failure? III. Antagonist's viewpoint.
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Adrenergic beta-Agonists↗
Phorbol ester increases the dihydropyridine-sensitive calcium conductance in a vascular smooth muscle cell line.
In vascular smooth muscle, phorbol esters cause a slowly developing contraction and an associated transmembrane calcium flux, both of which are inhibited by dihydropyridine calcium channel antagonists. In the A7r5 cultured vascular cell line, we used the whole-cell voltage-clamp technique to identify voltage-dependent calcium conductances and investigate the effect of phorbol esters on that conductance having characteristic dihydropyridine sensitivity (slowly inactivating, high-threshold, "L-type"). With barium as the charge carrier, large-amplitude (100-800 pA) inward currents of two types were characterized by their kinetics and voltage dependence. With holding potential--80 mV, a rapidly inactivating, low-threshold current ("T-type") was activated by depolarizations above-40 mV and was maximal at -10 mV. With holding potential -30 mV, this component was inactivated, and a second slowly inactivating, high-threshold current was activated above -10 mV and was maximal at +10 to +20 mV. These currents are similar to the T-type and L-type currents previously described in vascular smooth muscle cells. When added to the bath, the active phorbol ester, 12-O-tetradecanoyl phorbol-13-acetate (100 nM) increased the slowly inactivating (L-type) current by 32 +/- 20% (n = 8, +/- SD). Phorbol-12,13-dibutyrate (100 nM) caused a similar effect, but the inactive phorbol, 4-alpha-phorbol (100 nM), did not. We conclude that at least two distinct calcium conductances are expressed in A7r5 vascular smooth muscle cells, and that the dihydropyridine-sensitive calcium conductance is acutely modulated by phorbol esters, presumably acting through stimulation of protein kinase C. Such modulation may play a role in increasing transmembrane calcium influx mediated by agonist-receptor interactions that lead to activation of protein kinase C and may help to sustain or amplify calcium-dependent cell responses.
Animals↗
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.
Catecholamines↗
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.
Adult↗
Usefulness of calcium antagonists for congestive heart failure.
In patients with congestive heart failure (CHF) due to dilated cardiomyopathy, nifedipine, diltiazem and several of the newer calcium antagonists including nicardipine, nitrendipine, felodipine and PN 200-110 (isradipine) improve left ventricular function. Because of its relatively more pronounced negative inotropic and chronotropic actions, verapamil is generally not tolerated by patients with left ventricular failure. In addition, even relatively vascular-selective agents such as nifedipine can occasionally cause significant left ventricular depression, particularly if combined with beta-adrenergic blocking agents. Comparative studies using nitroprusside to cause an equivalent decrease in arterial pressure indicate that nifedipine acts predominantly on the arterial vasculature, and that a small but significant decrease in contractility occurs, apparently due to a direct myocardial action. Although diltiazem causes a depression in myocardial contractility in dogs with volume overload heart failure, limited data show no significant negative inotropic action in patients with heart failure. The negative inotropic effects, if any, of newer and possibly more vascular-selective agents are not yet known. Calcium antagonists appear to act predominantly on the limb and coronary vasculature, with relatively less effect on renal and hepatic vessels. In patients with CHF, nifedipine causes an increase in coronary blood flow and a decrease in the aorto-coronary sinus oxygen difference indicating an improvement in myocardial energetics. Although nifedipine causes an increase in cardiac index and decreases in systemic vascular resistance and pulmonary capillary wedge pressure during exercise, the limited data available fail to show a short- or long-term increase in exercise capacity. Nifedipine causes an increase in plasma renin activity, possibly due to a direct action on the kidney.(ABSTRACT TRUNCATED AT 250 WORDS)
Calcium Channel Blockers↗
Relationship of cardiac chamber volume to baroreflex activity in normal humans.
The objectives of this study were to examine the effect of incremental lower body negative pressure (LBNP) on cardiac chamber volume and assess the relationship between cardiac chamber volume and baroreflex activation of the neurohormonal axis. Accordingly, echocardiographic determination of cardiac chamber volume and neurohormonal responses were studied in 14 normal subjects during incremental LBNP. LBNP -10 mm Hg decreased left atrial diameter and left ventricular systolic volume index, but did not alter heart rate, systolic or pulse pressure, or stroke volume. During LBNP -10 mm Hg, plasma norepinephrine levels increased, suggesting activation of the sympathetic nervous system. LBNP -40 mm Hg caused a significant decrease in left atrial diameter and left ventricular systolic, diastolic, and stroke volume indices. During LBNP -40 mm Hg, heart rate increased, and systolic and pulse pressure fell. With this more negative level of LBNP, norepinephrine, angiotensin II, aldosterone, and arginine vasopressin concentrations and PRA all increased. The findings that left atrial diameter decreased and plasma norepinephrine concentration increased during LBNP -10 mm Hg suggest that the sympathetic nervous system is sensitive to changes in atrial receptor activity. At higher levels of LBNP (-40 mm Hg), activation of the renin-angiotensin system and release of vasopressin were associated with a fall in left ventricular diastolic volume as well as a decrease in the pressure input to the arterial baroreceptors. Under this condition, the differential contribution of the cardiopulmonary and arterial baroreceptors to the regulation of the renin-angiotensin system and vasopressin release cannot be distinguished.
Adult↗
Periodic breathing during exercise in severe heart failure. Reversal with milrinone or cardiac transplantation.
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Cheyne-Stokes Respiration↗
Phorbol ester-stimulated bidirectional transmembrane calcium flux in A7r5 vascular smooth muscle cells.
In A7r5 vascular smooth muscle cells, the phorbol ester 12-O-tetradecanoyl phorbol-13-acetate (TPA) caused a marked increase in the rate of unidirectional Ca2+ influx and a 63 +/- 9% increase in net 30-min 45Ca2+ uptake. Maximal TPA-stimulated 45Ca2+ uptake occurred at concentrations less than or equal to 3 nM and was equivalent to the maximal uptake stimulated by 55 mM KCl or 1 microM Bay k 8644. TPA-stimulated Ca2+ uptake was not additive to KCl- or Bay k 8644-stimulated uptake, and was inhibited by verapamil (100 microM), nitrendipine (1 microM), or high concentrations of Bay k 8644 (greater than or equal to 10 microM). The biologically inactive phorbol ester 12-O-tetradecanoyl phorbol-13-acetate methyl ether (10 nM) had no effect on 45Ca2+ uptake. TPA caused a 43 +/- 12% increase in Ca2+ efflux in 30 min, and exposure to TPA (10 nM) for 5 and 30 min caused no significant change in net cellular Ca2+ content as determined by radioisotopic equilibration or atomic absorption spectroscopy. TPA caused no apparent change in intracellular free Ca2+ concentration as determined with quin 2. Thus, in A7r5 cells, TPA causes a marked increase in Ca2+ influx through channels with the pharmacological characteristics of dihydropyridine-sensitive, voltage-dependent channels. This TPA-stimulated Ca2+ uptake is associated with increased Ca2+ efflux and no significant change in net cellular Ca2+ content or intracellular free Ca2+ concentration.
3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
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)
Blood Pressure↗
New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 2.
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3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
New positive inotropic agents in the treatment of congestive heart failure. Mechanisms of action and recent clinical developments. 1.
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Adenylyl Cyclases↗
Exercise responses before and after long-term treatment with oral milrinone in patients with severe heart failure.
Administration of the positive inotropic vasodilator milrinone results in immediate improvement in the maximal and submaximal metabolic responses to exercise. To determine whether these effects persist during long-term therapy, nine patients with severe congestive heart failure were evaluated by upright maximal exercise testing before therapy (baseline), after 10 +/- 1 weeks of oral therapy, and during double-blind, placebo-controlled readministration of intravenous milrinone after withdrawal of oral drug for 24 hours. During long-term oral therapy, maximal oxygen uptake was unchanged (baseline 792 +/- 72 ml per minute, oral therapy 820 +/- 83 ml per minute), whereas the anaerobic threshold was increased significantly from 570 +/- 53 ml per minute to 681 +/- 61 ml per minute. After withdrawal of milrinone, maximal oxygen uptake and anaerobic threshold decreased significantly; subsequent intravenous administration caused significant increases in maximal oxygen uptake and anaerobic threshold, back to the values measured during oral therapy. After oral milrinone withdrawal, maximal oxygen uptake decreased below baseline values, suggesting progression of the underlying disease. The anaerobic threshold expressed as a percent of maximal oxygen uptake was significantly increased during oral therapy (baseline 73 +/- 2 percent, oral therapy 84 +/- 2 percent) and remained significantly increased after drug withdrawal, suggesting a peripheral circulatory effect. These results indicate that in selected patients with severe congestive heart failure, milrinone exerts persistent effects on the metabolic responses to both maximal and submaximal exercise. Because of progressive deterioration in exercise capacity during long-term oral therapy, the effects of milrinone may not be apparent unless it is withdrawn. The relation of milrinone therapy to disease progression is not known.
Administration, Oral↗
Role of reflex sympathetic withdrawal in the hemodynamic response to an increased inotropic state in patients with severe heart failure.
Newer positive inotropic agents used in the treatment of severe heart failure not only increase cardiac contractility, but also cause peripheral vasodilation. It is not known to what extent this vasodilation is due to a direct peripheral action of the drug, as opposed to reflex withdrawal of sympathetic tone secondary to an augmented inotropic state. In 16 patients with severe heart failure, a 48 hour intravenous infusion of milrinone, a positive inotropic vasodilator drug, resulted in an increase in stroke volume index from 26 +/- 2 to 34 +/- 3 ml/m2 (p less than 0.001), a reduction in forearm vascular resistance measured by venous plethysmography from 43 +/- 5 to 27 +/- 3 U (p less than 0.003) and an increase in forearm venous capacitance from 2.1 +/- 0.2 to 2.9 +/- 0.2 ml/100 ml (p less than 0.001). To determine whether a withdrawal of sympathetic tone contributed to this vasodilation, milrinone was infused directly into the left main coronary artery in eight of the patients, thereby eliminating any direct vascular effects of the drug. Intracoronary milrinone (50 micrograms/min) caused an increase in peak positive first derivative of pressure (658 +/- 49 to 784 +/- 68 mm Hg/s; p less than 0.01) and stroke volume index (20 +/- 2 to 25 +/- 3 ml/m2; p less than 0.0001), which was associated with a reduction in plasma norepinephrine from 540 +/- 101 to 423 +/- 90 pg/ml (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Drug Administration Schedule↗
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.
Administration, Oral↗
Norepinephrine-induced alteration in the coupling of alpha 1-adrenergic receptor occupancy to calcium efflux in rabbit aortic smooth muscle cells.
To determine whether alpha-adrenergic desensitization of vascular smooth muscle is due to an alteration in alpha 1-adrenergic receptor coupling, we determined the relationship between receptor occupancy and maximal receptor-coupled Ca2+ efflux in cultured rabbit aortic smooth muscle cells (i) under basal conditions as defined by receptor inactivation with phenoxybenzamine and (ii) after 48 hr of exposure to several concentrations of 1-norepinephrine (NE). Neither phenoxybenzamine nor NE exposure caused a change in binding affinity for [3H]prazosin or NE. Maximal [3H]prazosin binding capacity and maximal NE-stimulated 45Ca2+ efflux decreased progressively with exposure of incubated cells to increasing concentrations of phenoxybenzamine or NE. An approximately 80% decrease in maximal [3H]prazosin binding capacity caused by either phenoxybenzamine or NE resulted in complete loss of NE-stimulated 45Ca2+ efflux, indicating that under these conditions approximately 20% of alpha 1-adrenergic receptors are not coupled to the Ca2+ efflux. Under basal conditions, the relationship between maximal [3H]prazosin binding capacity and maximal NE-stimulated 45Ca2+ efflux was markedly nonlinear, so that a near maximal response could be elicited by occupancy of only approximately 40% of the receptors. In contrast, after a 48-hr incubation of cells with NE, occupancy-response coupling was considerably less efficient, so that even full occupancy of the 35% of receptors that remained after NE exposure resulted in only approximately 20% of maximal NE-stimulated 45Ca2+ efflux. Thus, an alteration in occupancy-response coupling at a step proximal to Ca2+ mobilization and/or influx, rather than a reduction in receptor number, is of primary importance in the process of agonist-induced alpha-adrenergic receptor desensitization of vascular smooth muscle cells.
Animals↗
Separation of the direct myocardial and vasodilator actions of milrinone administered by an intracoronary infusion technique.
To determine the relative contributions of milrinone's positive inotropic and vasodilator actions in patients with severe congestive heart failure, the drug was administered by constant infusion directly into the left main coronary artery of 11 patients with New York Heart Association functional class III or IV heart failure. Intracoronary infusion of milrinone at rates up to 50 micrograms/min had no effect on mean arterial pressure or systemic vascular resistance but resulted in dose-related increases in peak positive dP/dt (+21%), stroke volume index (+18%), and stroke work index (+21%) and decreases in heart rate (-3%), mean right atrial pressure (-25%), and left ventricular end-diastolic pressure (-17%). In eight patients, intravenous administration (75 micrograms/kg) after the intracoronary infusion resulted in significant decreases in mean arterial pressure (-14%) and systemic vascular resistance (-40%), further increase in stroke volume index compared with intracoronary administration, and further decreases in mean right atrial and left ventricular end-diastolic pressures compared with intracoronary administration. These data indicate that milrinone exerts both positive inotropic and vasodilator actions that contribute significantly to the drug's overall hemodynamic effect.
Adult↗