Effects of intracoronary infusion of an inotropic agent, E-1020 (loprinone hydrochloride), on cardiac function: evaluation of left ventricular contractile performance using the end-systolic pressure-volume relationship (original) (raw)
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Journal of applied physiology (Bethesda, Md. : 1985), 2016
Inotropic medications are routinely used to increase cardiac output and arterial blood pressure during critical illness. However, few comparative data exist between these medications, particularly independent of their effects on venous capacitance and systemic vascular resistance. We hypothesized that an isolated working heart model that maintained constant left atrial pressure and aortic blood pressure could identify load-independent differences between inotropic medications. In an isolated heart preparation, the aorta and left atrium of Sprague Dawley rats were cannulated and placed in working mode with fixed left atrial and aortic pressure. Hearts were then exposed to common doses of a catecholamine (dopamine, epinephrine, norepinephrine, or dobutamine), milrinone, or triiodothyronine (n = 10 per dose per combination). Cardiac output, contractility (dP/dtmax), diastolic performance (dP/dtmin and tau), stroke work, heart rate, and myocardial oxygen consumption were compared during...
Circulation, 1988
Clinical trials in patients with dilated cardiomyopathy (DCM) have shown a wide disparity in the hemodynamic responses to positive inotropic therapy. In addition, the response of the failing left ventricle to positive inotropic agents reflects the net interaction of multiple factors, including the magnitude of contractile abnormality and compensatory mechanisms. In the current study, left ventricular geometry, loading conditions, and contractile state were assessed in 13 patients with nonischemic DCM with the use of simultaneous high-fidelity pressure measurements and echocardiographic recordings. Comparisons were made with echocardiographic and calibrated carotid pulse data acquired in nine age-matched normal subjects. The patients with DCM were divided according to the left ventricular end-diastolic wall thickness-to-dimension ratio into groups with "appropriate" hypertrophy (i.e., < 2 SDs from mean normal; n = 5; group 1) and "inadequate" hypertrophy (i.e., > 2 SDs from mean normal; n =8; group 2). Age, New York Heart Association functional class, left ventricular wall mass index, and left ventricular end-diastolic pressure and dimension were similar for the DCM groups. Baseline left ventricular afterload (defined as circumferential end-systolic wall stress, COes) was 168% and 203% greater than normal in groups 1 and 2, respectively. The administration of the 13-adrenoceptor agonist dobutamine decreased left ventricular afterload by 12% in the normal subjects and by 10% in group 1 patients, while augmenting afterload by 5% in group 2 patients. The latter response occurred despite a 17% fall in systemic vascular resistarnce. Overall left ventricular performance, as assessed by the rate-corrected mean velocity of fiber shortening (Vcfc), was related to left ventricular afterload (i.e., Ces). The resultant Qes -Vcfc relationship, a sensitive measure of left ventricular contractility, was determined over a wide range of afterload conditions generated by methoxamine (normal subjects) or nitroprusside (DCM). Baseline left ventricular contractile state was 61% of normal for group 1 and 44% of normal for group 2. The contractile response to dobutamine infusion was 52% of normal for group 1 and only 22% of normal for group 2. Thus, positive inotropic therapy with dobutamine in patients with DCM is limited by (1) an attenuated contractile response and (2) elevated left ventricular afterload, which may be augmented further during its administration. The ability to separate and quantify abnormalities in left ventricular geometry, loading conditions, and contractile state allows a more thorough interpretation of the hemodynamic responses to a positive inotropic agent and may be useful in determining which patients with heart failure would benefit from treatment with specific cardiotonic agents. trials have demonstrated a wide disparity in the hemodynamic responses to these agents even when administered in the same doses to patients with similar symptoms.3 This is due to numerous factors, including (1) interpatient differences in left ventricular contractile state, preload, afterload, heart rate, chamber geometry, and ventricular hypertrophy,6' 7 (2) the variable activation of cardiac and peripheral vascular receptors by the same pharmacologic agent, and (3) the load dependency of traditional measures of overall left ventricular performance (e.g., cardiac output and ejection fraction) as well as their inability to distinguish 625 by guest on July 11, 2011 http://circ.ahajournals.org/ Downloaded from
Circulation, 1986
Symptoms of congestive heart failure frequently reflect abnormalities in both systolic and diastolic performance. While much work has been reported regarding the mechanisms by which positive inotropic and vasodilator therapy affect systolic performance, little is known about their effect on diastolic function. In 12 patients with diffuse congestive cardiomyopathy micromanometer left ventricular and aortic pressure measurements were recorded simultaneously with two-dimensionally targeted M mode echocardiograms and thermodilution-determined cardiac output. Each patient received dopamine (2, 4, and 6 gg/kg/min), and dobutamine (2, 6, and 10 ,ug/kg/min), and 10 received nitroprusside (0.125 to 2.0 gg/kg/min). Baseline hemodynamics were characterized by low cardiac index (2.1 ± 0.7 liter/min/m2, mean ± SD), high left ventricular end-diastolic pressure (24 ± 10 mm Hg), and increased end-diastolic (6.8 + 1.0 cm) and end-systolic dimensions (6.0 1.0 cm). All patients had abnormal left ventricular pressure decay with a prolonged time constant (67 ± 20 msec) and reduced peak diastolic lengthening rates. Dopamine and dobutamine decreased the time constant of relaxation and increased the peak lengthening rate. Dobutamine also reduced the minimum diastolic pressure from 14 ± 7 to 10 + 9 mm Hg (p < .01); neither drug reduced end-diastolic pressure. In fact, dopamine elevated end-diastolic pressures in seven patients, despite more rapid pressure decay. Diastolic pressure-dimension relations after dopamine and dobutamine showed a leftward shift with a reduced end-systolic chamber size, but no significant changes in passive chamber stiffness. Nitroprusside decreased left ventricular minimum diastolic pressure by 4 ± 2 mm Hg and end-diastolic pressure by 7 ± 4 mm Hg (p < .0 1). It did not consistently accelerate left ventricular pressure decay at the doses tested. The decreased end-diastolic pressure with nitroprusside was due to a reduced end-diastolic dimension in five patients. In the other patients, all of whom had elevated right atrial pressures, diastolic pressure-dimension relations showed a parallel downward shift after nitroprusside. Thus, positive inotropic therapy with /31-adrenoceptor agonists enhances early diastolic distensibility by accelerating relaxation, augmenting filling, and reducing end-systolic chamber size. Vasodilator therapy is much more effective in lowering diastolic pressures. In some patients this is due to a reduction in extrinsic restraint of the pericardium and/or right ventricular interaction, while in others it simply reflects a decrease in chamber size without alterations in ventricular passive chamber properties. Circulation 74, No. 4, 815-825, 1986. AS OUR UNDERSTANDING of the pathophysiology of the heart failure syndrome has improved, certain classes of drugs have assumed prominent roles in its treatment. The administration of vasodilating agents is
Electrophysiologic and proarrhythmic effects of intravenous inotropic agents
Progress in Cardiovascular Diseases, 1995
intravenous inotropic agents promote increased myocardial contractility via elevation of myocyte calcium concentrations, a mechanism that is also known to promote the development of cardiac arrhythmias. The purpose of this article is to review the electrophysiologic effects and relative potential for proarrhythmia associated with dobutamine, dopamine, and the phosphodiesterase inhibitors amrinone and milrinone. Dobutamine increases sinoatrial node automaticity and decreases atrial and atrioventricular (AV) node refractoriness and AV nodal conduction time. The drug also decreases ventricular refractoriness in both healthy and ischemic myocardium. Dobutamine has been shown to increase heart rate in a dose-related fashion in animals and in humans. In humans, dobutamine has been reported to induce ventricular ectopic activity (VEA) in 3% to 15% of patients, although VEAs are often asymptomatic, requiring no intervention. Ventricular tachycardia (VT) associated with dobutamine appears to occur rarely. Patients with underlying arrhythmias or heart failure or those receiving excessive doses of dobutamine are at greatest risk for proarrhythmia. Dopamine increases automaticity in Purkinje fihers and has a biphasic effect on action potential duration. Dopamine has been reported to induce atrial or ventricular arrhythmias in animals. In humans, dopa-mine may be associated with dose-related sinus tachycardia but has also been reported to cause VEA, which is usually asymptomatic. Dopamine-associated VT appears to occur rarely. Dopamine produces greater elevations in heart rate or frequency of ventricular premature beats at a given value of cardiac index than does dobutamine. The phosphodiesterase inhibitors amrinone and milrinone increase conduction through the AV node and decrease atrial refractoriness.
Journal of the American College of Cardiology, 1998
Objectives. We sought to determine the precise myocardial effects of OPC-18790 as demonstrated by intracoronary administration. Background. Although previous studies have determined the cardiovascular effects of a novel intravenous inotrope, OPC-18790, the observed benefits on contractile and diastolic function may have been confounded by the marked changes in peripheral loading associated with this drug when given intravenously. Methods. Eight heart failure patients received intracoronary OPC-18790 at 31.25 g/min for 20 min, and then at 62.5 g/min for another 20 min. Hemodynamic variables and pressure-volume indexes using the conductance catheter method were determined at baseline and then after the two doses. Results. There were no significant effects on heart rate, cardiac output or loading conditions, including afterload as determined by systemic vascular resistance and arterial elastance (E a) and preload as determined by end-diastolic volume (EDV). There were significant increases in end-systolic elastance (E es) from 0.74 ؎ 0.11 to 0.90 ؎ 0.16 mm Hg/ml at 31.25 g/min and to 1.37 ؎ 0.33 mm Hg/ml at 62.5 g/min (p < 0.05 by analysis of variance [ANOVA]). Diastolic function improved, as determined by the time constant for isovolumetric relaxation tau, which decreased significantly from baseline to 31.25 g/min (94 ؎ 9 to 79 ؎ 9 ms, p < 0.05), and did not shorten further at 62.5 g/min (78 ؎ 8 ms, p ؍ NS). There were significant decreases in right atrial pressure (9 ؎ 1 to 7 ؎ 1 mm Hg, p < 0.01 by ANOVA) and mean pulmonary artery wedge pressure (21 ؎ 3 to 16 ؎ 2 mm Hg, p < 0.05 by ANOVA). This fall in filling pressures was not accompanied by any change in EDV. Inspection of the diastolic portion of the pressure-volume curve confirmed a downward shift consistent with pericardial release in five of the eight patients. Conclusions. Intracoronary administration of OPC-18790 demonstrates that the direct myocardial effects of this agent include a modest increase in inotropy and improvement in diastolic function, both of which occur without increases in heart rate, indicating that this agent may be beneficial for the intravenous treatment of congestive heart failure.
British Journal of Clinical Pharmacology, 1990
The haemodynamic effects of a new cardioselective postsynaptic a 1-adrenoceptor antagonist UK-52,046, were evaluated in 25 patients with stable coronary disease, with or without impaired left ventricular function. At rest the haemodynamic effects to two doseresponse regimens were determined. In an initial eight patients 0.125, 0.125 and 0.25 ,ug kg-1 were administered peripherally at 15 min intervals; the haemodynamic measurements were determined between 10 to 15 min after each dose. In a further 17 patients, the dose regimen was doubled yielding a cumulative dose-regimen of 0.25, 0.5 and 1.0 ,ug kg-1. The exercise effects were determined by comparison of measurements during 4 min of supine sub-maximal bicycle exercise at a fixed workload before and after drug treatment. 2 At rest, the lower dose regimen of UK-52,046 significantly reduced systemic mean arterial blood pressure (-5 mm Hg; P < 0.05) and increased cardiac index (+ 0.21 min-' m-2, P < 0.01). The higher dose regimen of UK-52,046 reduced systemic mean arterial blood pressure (-7 mm Hg; P < 0.01), pulmonary artery occluded pressure (PAOP) (-2 mm Hg, P < 0.01) and vascular resistance index (-314 dyn s cm-5 M2; P < 0.05) with an increase in heart rate (+ 7%, P < 0.05) and cardiac index (+ 0.2 1 min-' m-2, P < 0.05). 3 During dynamic exercise, low dose UK-52,046 did not change the haemodynamics significantly. High dose UK-52,046 reduced systemic mean arterial blood pressure (-5.9 mm Hg, P < 0.01), PAOP (-8.5 mm Hg, P < 0.01), systemic vascular resistance index (-281 dyn s cm-5 m2, P < 0.01) and increased cardiac index (+0.81 min-' m-2, P < 0.01). Comparing haemodynamic response in patients whose initial PAOP > 18 mm Hg with those below did not demonstrate any apparent difference in haemodynamic response related to the presence or absence of left ventricular functional impairment. 4 Thus, UK-52,046 was haemodynamically safe in coronary artery disease; during exercise-induced heart failure beneficial effects on preload and cardiac pumping activity were evident.
Amer Heart J, 1996
p-blockers reduce infarct size and improve survival after acute myocardial infarction (MI). Post-MI angiotensin-converting enzyme inhibition also improves survival and may attenuate left ventricular (LV) dilatation. We evaluated the effect of early enalapril treatment on LV volumes and ejection fraction (EF) in patients on concomitant p-blockade after MI. Intravenous enalaprilat or placebo was administered <24 hours after MI and was continued orally for 6 months. LV volumes were assessed by echocardiogrephy 3 _+ 2 days, 1 and 6 months after MI. Change in LV diastolic volume during the first month was attenuated with enalapril (2.7 vs placebo 6.5 ml/m 2 change; p < 0.05), and significantly lower LV diastolic and systolic volumes were observed with enalapril treatment compared with placebo at I month (enalaprU 47.2/ 23.9 vs placebo 53.1/29.2 ml/m2; p < 0.05) and at 6 months (enalapril 47.9/24.8 vs placebo 53.8/29.6 ml/m~; p < 0.05). EF was also significantly higher 1 month after MI in these patients (enalapril 50.4% vs placebo 46.4%; p < 0.05). Our data demonstrate that early enalapril treatment attenuates LV volume expansion and maintains lower LV volumes and higher EF in patients receiving concurrent 13-blockade after MI. A possible additive effect of combined therapy should be evaluated prospectively. (Am Heart J 1996;132:71-7.) Treatment for patients with acute myocardial infarction (MI) has improved substantially during the past few years, resulting in significant reduction in post-infarction morbidity and death. 1 B-blockers re-