Recent developments in the treatment of congestive heart failure.
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Adrenergic beta-Antagonists↗
Biomedical subjects
W B Hood
Publications and source records attributed to W B Hood.
Controlled and uncontrolled studies of phosphodiesterase III inhibitors in contemporary cardiovascular medicine.
The phosphodiesterase inhibitors are new inotrope vasodilators that have beneficial hemodynamic effects in patients with congestive heart failure (CHF). The most extensively studied agents are milrinone and enoximone. Both drugs have clearly been shown in numerous studies to improve hemodynamics in patients with CHF when given acutely by either the intravenous or oral route. In long-term studies, milrinone has been shown to have sustained beneficial hemodynamic effects during active treatment. Effects on exercise tolerance have been less clear-cut in several uncontrolled trials, but a recent large-scale randomized trial does show sustained improvement in exercise performance. When milrinone is withdrawn after long-term therapy, some studies show worsened cardiac performance; the exact cause remains ill-defined, but could be due to deterioration of baseline ventricular function or to "rebound." Both uncontrolled studies and a large recently reported randomized trial show that the hemodynamic response to readministration of milrinone after withdrawal is well-preserved, i.e., no tolerance is observed. Studies of enoximone show that its acute hemodynamic effects are similar to those of milrinone, but its long-term efficacy, using both hemodynamic and exercise end points, is less clear-cut, and no large-scale randomized trials of enoximone therapy have yet been reported. The studies of both these agents performed thus far indicate that the phosphodiesterase inhibitors have considerable promise for both acute and long-term treatment of patients with CHF.
Clinical Trials as Topic↗
Effects of pinacidil on myocardial blood flow and infarct size after acute left anterior descending coronary artery occlusion and reperfusion in awake dogs with and without a coexisting left circumflex coronary artery stenosis.
To determine whether partial stenosis of a second major coronary artery promoted vasodilator-induced coronary steal and increased infarct size after acute coronary artery occlusion, we produced acute myocardial infarction by 4-h left anterior descending coronary artery occlusion and 20-h reperfusion in awake dogs with and without a mild to moderate stenosis (33-72%) of the proximal left circumflex coronary artery. Dogs were randomized to receive intravenous (i.v.) normal saline or pinacidil, a new antihypertensive agent with a marked coronary dilator property, beginning 40 min after onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Pinacidil was titrated to decrease mean aortic pressure 25 mm Hg, which resulted in an increase in heart rate (HR), cardiac output (CO), and left ventricular (LV) dP/dt and LVdP/dt/P. Saline infusion had no effects. Blood flows to ischemic and remote myocardium did not differ between dogs with and without coronary stenosis. Pinacidil increased blood flow threefold in normal myocardium, but had no effect on infarct zone myocardial blood flow or infarct size (58 +/- 4% of region at risk vs. 56 +/- 4% in animals receiving normal saline) in dogs without coronary stenosis. In contrast, similar administration of pinacidil in dogs with coronary stenosis reduced infarct size zone myocardial blood flow and increased infarct size (69 +/- 3% vs. 55 +/- 5% in the saline group, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Comparative effects of nitroprusside and pinacidil on myocardial blood flow and infarct size in awake dogs with acute myocardial infarction.
The effect of nitroprusside in limiting myocardial infarct was compared with that of pinacidil, a new antihypertensive agent with potent coronary vasodilator properties, in instrumented awake dogs subjected to 4 hr of left anterior descending coronary artery occlusion and 20 hr of reperfusion. Dogs were randomly assigned to receive intravenous normal saline, nitroprusside, or pinacidil beginning 40 min after the onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Nitroprusside and pinacidil were titrated to decrease mean aortic pressure by 25 mm Hg; normal saline had no effect on mean aortic pressure. Other systemic hemodynamic variables were not significantly altered by normal saline or nitroprusside, and myocardial blood flow did not change during normal saline infusion in normal and ischemic myocardium. In contrast, nitroprusside increased the blood flow and the endocardial/epicardial flow ratio in ischemic myocardium. This increase in ischemic myocardial blood flow was accompanied by a significant reduction in infarct size (40 +/- 3% of region at risk vs 58 +/- 4% in the normal saline group; p less than .05). Pinacidil increased heart rate, cardiac output, and the peak rate of rise of left ventricular pressure. Furthermore, despite causing a threefold to fourfold increase in normal myocardial blood flow, pinacidil had no effect on either blood flow to ischemic myocardium or infarct size (57 +/- 5%). The data indicate that the marked coronary vasodilator effect of pinacidil does not cause an increase in ischemic blood flow or a reduction in infarct size.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Short-term hemodynamic effects of vasopressin V1-receptor inhibition in chronic right-sided congestive heart failure.
Arginine vasopressin is elevated in congestive heart failure. To determine the effect of arginine vasopressin upon systemic hemodynamics and regional blood flows, we administered the specific inhibitor of the vascular action of vasopressin [1-(beta-mercapto-beta,beta-cyclopentamethylenepropionic acid),2-(O-methyl)-tyrosine]-arginine vasopressin [d(CH2)5Tyr(Me)AVP] to 15 dogs with chronic right-heart failure produced by tricuspid avulsion and progressive pulmonary artery constriction. The animals exhibited increased plasma arginine vasopressin and norepinephrine levels. Vasopressin inhibition increased cardiac output and left ventricular dP/dt and dP/dt/P, and it decreased total peripheral vascular resistance, whereas mean aortic pressure did not change significantly. Simultaneously, blood flow increased to skeletal muscle, kidneys, skin, and right and left ventricular myocardium. Plasma catecholamines also increased. Pretreatment with propranolol and prazosin abolished the increases in cardiac output and left ventricular function produced by vasopressin inhibition. Pretreatment also led to a decrease in mean aortic pressure after vasopressor inhibition. In contrast, administration of d(CH)2)5Tyr(Me)AVP to 11 sham-operated animals or administration of normal saline to nine sham-operated and eight heart-failure dogs was without effect either in the absence or in the presence of adrenergic receptor blockade. Thus, arginine vasopressin participates in the control of the circulation in right-sided congestive heart failure, with both a direct constrictor action on blood vessels and an indirect action by inhibition of the sympathetic nervous system.
Animals↗
Hemodynamic and regional blood flow response to milrinone in patients with severe congestive heart failure: a dose-ranging study.
This study was undertaken to assess the hemodynamic efficacy, changes in regional blood flow, and safety of milrinone over a range of intravenous bolus injections (12.5 to 125 micrograms/kg), a continuous 18-hour infusion (0.2 to 0.7 microgram/kg/min), and following oral administration. All eighteen patients with New York Heart Association class III or IV congestive heart failure demonstrated hemodynamic improvement following intravenous bolus therapy. Dose-related increases in cardiac index occurred, ranging from a 12 +/- 6% increase following a 12.5 micrograms/kg bolus to a 37 +/- 10% increase after 75 micrograms/kg. Pulmonary wedge pressure fell 17 +/- 5% following 12.5 micrograms/kg and 28 +/- 9% following 75 micrograms/kg. Little change was apparent during the continuous infusion except for a late increase in cardiac index, but similar changes occurred in response to a single oral dose. Forearm blood flow increased significantly after 3 hours in the two higher infusion groups, but there was no consistent change in hepatic blood flow. We conclude that hemodynamic parameters and forearm blood flow are improved in patients with severe congestive heart failure following intravenous and short-term oral milrinone therapy.
Administration, Oral↗
Effects of milrinone on systemic hemodynamics and regional circulations in dogs with congestive heart failure: comparison with dobutamine.
Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.
Animals↗
Systemic and regional hemodynamic effects of isomazole in awake dogs with congestive heart failure.
To determine the hemodynamic effects of isomazole, an imidazopyridine, we administered isomazole (10 and 20 micrograms/kg/min) to 10 awake dogs with right-sided congestive heart failure produced by pulmonary artery constriction and tricuspid valve avulsion. Isomazole increased cardiac output, heart rate, right ventricular and left ventricular (LV) dP/dt, LVdP/dt/P and decreased aortic pressure and total peripheral vascular resistance. Simultaneously, blood flow increased to myocardium, quadriceps muscle, brain and splanchnic beds, whereas vascular resistance decreased. Furthermore, isomazole increased LV oxygen consumption and decreased transcoronary arteriovenous oxygen difference. Similar administration of normal saline had no effects. Angiotensin II was infused to restore mean aortic pressure to base-line values during isomazole infusion; however, despite the return of aortic pressure to base-line values, cardiac output, LVdP/dt and LVdP/dt/P remained elevated. The systemic and regional hemodynamic effects of isomazole were unaffected by pretreatment with propranolol and mecamylamine. Thus, isomazole exerted positive inotropic, chronotropic and vasodilator effects in congestive heart failure dogs. The inotropic effect of isomazole was independent of the decrease in aortic pressure, and the hemodynamic effects of isomazole were not mediated via the autonomic nervous system. Furthermore, the decrease in transcoronary arteriovenous oxygen difference suggests that isomazole exerted an active coronary vasodilator action which may improve myocardial oxygen demand/supply ratio.
Angiotensin II↗
Pharmacokinetics of the bipyridines amrinone and milrinone.
The pharmacokinetics of milrinone were studied in sequential ascending doses in New York Heart Association Class III and IV patients receiving oral and intravenous medication. The parameters determined after parenteral administration were estimated by fitting the plasma concentration data to an open two-compartment body model. After oral medication, regression-independent parameters were determined. After either oral or parenteral administration of milrinone, plasma levels were dose dependent and the drug had an apparent first-order terminal elimination half-life of approximately 2 hr. The apparent volume of distribution was approximately 400 to 500 ml/kg, and total body clearance was approximately 130 ml/kg/hr. These values obtained in patients receiving milrinone were compared with those obtained for milrinone in volunteers, as well as those noted with the other inotropic bipyridine, amrinone. Milrinone's elimination from the blood stream patients was slower that that in normal healthy subjects and faster than amrinone's elimination in patients with congestive heart failure. Milrinone's pharmacokinetic parameters in these patients were unchanged after approximately 30 days of continuous oral medication.
Administration, Oral↗
Relationship of the lytic state to successful reperfusion with standard- and low-dose intracoronary streptokinase.
The influence of a systemic lytic state on reperfusion obtained after intracoronary streptokinase (SK) therapy has been evaluated in 15 patients with acute myocardial infarction and complete coronary occlusion. Coronary angiographic studies and measurements of blood fibrinolytic parameters were repeated at 15 min intervals during the infusion of a standard dose of SK and were compared with the results with approximately one-tenth the standard dose. Successful reperfusion was obtained in only 20% (2/10) of patients receiving the low dose, compared with a 75% to 80% success rate in patients receiving the standard dose as initial treatment (4/5) or as follow-up treatment of patients in whom low-dose therapy failed (6/8). There was a striking association between reperfusion and development of the lytic state in that all 12 treatments resulting in reperfusion also caused a lytic state and all seven treatments that failed to produce a lytic state also failed to induce reperfusion (p less than .001). Among the successfully treated patients, the dose of SK that induced a lytic state was relatively constant. However, coronary arterial thrombi differed in susceptibility to treatment. Sensitive thrombi (5/12) dissolved before the lytic state occurred and at a lower SK dose than that needed to cause a lytic state; more resistant thrombi (7/12) required a longer time and a significantly larger SK dose to dissolve. These results indicate that intrinsic properties of the thrombus influence the rate and outcome of treatment and that a minimal dose of SK (about 200,000 U) is required to ensure lasting reperfusion in susceptible patients.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Amiodarone pulmonary toxicity. Chest radiography and CT in asymptomatic patients.
Two asymptomatic patients from a group of 30 being treated with the antiarrhythmic drug amiodarone developed roentgenographic pulmonary and pleural reactions. Computed tomography in one patient with an uncommon radiographic pattern of fuzzy nodules showed the spatial distribution of the parenchymal changes, as well as unrecognized pleural thickening. The disease in these asymptomatic patients was presumably detected on the periodic chest roentgenogram at an early stage because the changes disappeared after withdrawal of the drug. Periodic chest radiographs are recommended during amiodarone therapy and CT may be useful in evaluation of patients with unusual chest radiographic findings.
Aged↗
Contrasting effects of dopamine and dobutamine on myocardial release of norepinephrine during acute myocardial infarction.
The effects of dopamine and dobutamine on release of norepinephrine from normal and ischemic myocardium were compared in 2 groups of open-chest anesthetized dogs. Both agents were infused intravenously at a rate of 10 micrograms/Kg/min for 2 hours, beginning 40 min after snare occlusion of the left anterior descending coronary artery. There were no major differences in hemodynamic responses between the 2 groups. Blood samples were taken simultaneously from the aorta, coronary sinus and the cardiac vein that ran parallel to the left anterior descending coronary artery before and after coronary artery occlusion. Plasma norepinephrine increased 40 min after the occlusion, with a net efflux in both coronary sinus and cardiac venous blood. Dopamine caused further increases in plasma norepinephrine. At 20 min after the beginning of dopamine infusion the coronary sinus concentration (4.09 +/- 1.36 ng/ml) was significantly greater than the arterial concentration (2.84 +/- 0.87 ng/ml). This transcardiac difference disappeared during continuous infusion 2 hours after coronary artery occlusion. Differences in norepinephrine concentration between the arterial and cardiac venous blood, however, were not significant. In contrast, plasma norepinephrine did not increase during dobutamine infusion in either the ischemic or non-ischemic bed. Thus, the results suggest that while these two agents have similar systemic hemodynamic effects, only dopamine increases myocardial release of norepinephrine from either ischemic or normal myocardium during acute myocardial infarction.
Animals↗
A predictive instrument to improve coronary-care-unit admission practices in acute ischemic heart disease. A prospective multicenter clinical trial.
Each year 1.5 million patients are admitted to coronary-care units (CCUs) for suspected acute ischemic heart disease; for half of these, the diagnosis is ultimately "ruled out." In this study, conducted in the emergency rooms of six New England hospitals ranging in type from urban teaching centers to rural nonteaching hospitals, we sought to develop a diagnostic aid to help emergency room physicians reduce the number of their CCU admissions of patients without acute cardiac ischemia. From data on 2801 patients, we developed a predictive instrument for use in a hand-held programmable calculator, which requires only 20 seconds to compute a patient's probability of having acute cardiac ischemia. In a prospective trial that included 2320 patients in the six hospitals, physicians' diagnostic specificity for acute ischemia increased when the probability value determined by the instrument was made available to them. Rates of false-positive diagnosis decreased without any increase in rates of false-negative diagnosis. Among study patients with a final diagnosis of "not acute ischemia," the number of CCU admissions decreased 30 per cent, without any increase in missed diagnoses of ischemia. The proportion of CCU admissions that represented patients without acute ischemia dropped from 44 to 33 per cent. Widespread use of this predictive instrument could reduce the number of CCU admissions in this country by more than 250,000 per year.
Adult↗
Nitroprusside infusion in experimental acute myocardial infarction with systemic hypertension: effects on systemic hemodynamics and regional myocardial blood flows.
The effects of graded doses of nitroprusside on regional myocardial blood flow were studied in awake, acutely hypertensive dogs with acute myocardial infarction. Acute systemic hypertension was produced by infusing a mixture of norepinephrine and epinephrine for 80 minutes after coronary artery occlusion. The increase in aortic pressure produced by catecholamine infusion was accompanied by increases in heart rate, left ventricular (LV) end-diastolic pressure, first derivative of LV pressure (dP/dt), dP/dt at an LV developed pressure of 50 mm Hg (dP/dt/P) and pressure-rate product, but total peripheral vascular resistance did not change significantly. Two graded doses of nitroprusside were then infused, each for 25 minutes, beginning 30 minutes after the onset of coronary artery occlusion. The smaller dose of nitroprusside returned aortic pressure to control levels and significantly reduced total peripheral vascular resistance and LV end-diastolic pressure, but did not affect cardiac output, heart rate, LV dP/dt, dP/dt/P and pressure-rate product. Regional blood flow increased to both the ischemic and normal myocardium. The larger dose of nitroprusside further reduced aortic pressure and total peripheral vascular resistance and LV end-diastolic pressure and significantly increased heart rate and cardiac output. However, LV dP/dt, dP/dt/P and pressure-rate product remained unchanged. Regional blood flow to normal myocardium increased, but the increase in ischemic endocardial blood flow produced by the smaller dose of nitroprusside was no longer significant when the larger dose was administered. These changes were not produced by administration of normal saline solution.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Sustained improvement of cardiac function in patients with congestive heart failure after short-term infusion of dobutamine.
Fifteen patients with congestive cardiomyopathy (six idiopathic and nine alcoholic) manifested by heart failure (New York Heart Association class III or IV) were randomly assigned to a protocol in which dobutamine (n = 8) or 5% dextrose in water (n = 7) was infused continuously for 72 hr. The dose of dobutamine was titrated to increase cardiac output to twice the baseline values. The patients were evaluated before infusion, shortly after infusion, and 1, 2, and 4 weeks thereafter. Functional class improved in six of eight dobutamine-treated patients but in only two of seven control patients during the 4 week observation period. Maximal exercise time and left ventricular ejection fraction increased significantly above baseline only in the dobutamine group. However, neither dobutamine nor placebo infusion produced significant changes shortly after infusion in heart rate, cardiac index, or total peripheral vascular resistance at rest or during exercise at similar workloads. The group receiving dobutamine did show a reduction in systemic systolic and pulmonary arterial mean and diastolic pressure at rest (123 +/- 5 to 108 +/- 6, 32 +/- 5, to 24 +/- 3, and 26 +/- 4 to 20 +/- 2 mm Hg, respectively). In addition, total body oxygen consumption during similar workloads was lower after dobutamine infusion than before.(ABSTRACT TRUNCATED AT 250 WORDS)
Catecholamines↗
Sensitivity of technetium-99m-pyrophosphate scintigraphy in diagnosing cardiac amyloidosis.
To determine the value of technetium-99m-pyrophosphate myocardial scintigraphy in the diagnosis of amyloid heart disease this procedure was prospectively performed in 20 consecutive patients with biopsy-proven primary amyloidosis. Eleven patients had echocardiographic abnormalities compatible with amyloid cardiomyopathy, 9 of whom had congestive heart failure. Diffuse myocardial pyrophosphate uptake was of equal or greater intensity than that of the ribs in 9 of the 11 patients with echocardiograms suggestive of amyloidosis, but in only 2 of the 9 with normal echocardiograms, despite abnormal electrocardiograms (p less than 0.01). Increased wall thickness measured by M-mode echocardiography correlated with myocardial pyrophosphate uptake (r = 0.68, p less than 0.01). None of 10 control patients with nonamyloid, nonischemic heart disease had a strongly positive myocardial pyrophosphate uptake. Thus, myocardial technetium-99m-pyrophosphate scanning is a sensitive and specific test for the diagnosis of cardiac amyloidosis in patients with congestive heart failure of obscure origin. It does not appear to be of value for the early detection of cardiac involvement in patients with known primary amyloidosis without echocardiographic abnormalities.
Aged↗
Comparison of dobutamine and dopamine in acute myocardial infarction. Effects of systemic hemodynamics, plasma catecholamines, blood flows and infarct size.
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Animals↗
Future directions for nonclinical evaluation.
Much of our knowledge about the effects of coronary occlusion and reperfusion is derived from studies in experimental animals. The recent discovery that coronary thrombosis is usually present in clinical myocardial infarction and that thrombolysis represents an approach to therapy presents opportunities for further experimental work. Animal models are particularly suited to the study of pathogenesis of thrombus formation in atherosclerotic vessels, the role of coronary vasomotor tone, and the effects of restoration of flow upon ischemic myocardium. Although the value of thrombolytic therapy must be proved in the clinical setting, animal models provide an important resource for the study of basic mechanisms.
Animals↗