Effect of quinidine on differing sensitivities of Purkinje fibers and myocardium to inhibition of monovalent cation transport by digitalis in dogs

Studies have implicated quinidine in increasing serum digoxin levels, resulting in serious arrhythmias. Arrhythmias caused by digitalis intoxication are thought to originate in Purkinje fibers. Thus, the extent of inhibition of monovalent cation-active transport in Purkinje fibers and myocardium may explain the enhanced toxicity of the combined administration of digoxin and quinidine. Monovalent cation transport was assessed by measuring the uptake of the potassium analog rubidium in samples of myocardium and Purkinje fibers after in vitro exposure to ouabain and after long-term administration of digoxin and quinidine or digoxin alone. A group of dogs received chronic digoxin administration and achieved a steady-stage digoxin level of 2.1 ± 0.3 ng/ml. Quinidine administered intravenously caused a 134% increase in the serum digoxin level. The transport in myocardium was unchanged, while it was reduced to 40% of control levels in Purkinje fibers. The difference in sensitivity between Purkinje fibers and myocardium may explain the finding that digitalis-toxic arrhythmias arise in Purkinje fibers and that quinidine, when combined with digitalis, increases the incidence of such arrhythmias.     

Hemodynamic comparison of intravenous amrinone and dobutamine in patients with chronic congestive heart failure

Amrinone, a new inotropic agent, has been shown to be beneficial in patients with congestive heart failure. However, its hemodynamic effects have not been compared with those of currently useful catecholamines. In this study, the effects of intravenously administered dobutamine and amrinone were compared in eight patients with severe chronic congestive heart failure. Dobutamine was infused until a maximal increase in cardiac index was reached or undesirable effects were produced. This dose was then continued for 8 hours. After a return of hemodynamic values to baseline level, amrinone was infused at a rate of 40 μg/kg per min for 1 hour and then 10 μg/kg per min for 24 hours. Both drugs significantly improved cardiac index while simultaneously decreasing systemic vascular resistance and right atrial and pulmonary wedge pressures (p <0.05). Initially no differences could be found between the drugs. However, with prolonged infusion amrinone produced a sustained improvement whereas dobutamine had a decreased effectiveness. Thus, amrinone is comparable in effect with the optimal dose of dobutamine and would appear to be an extremely promising drug in the acute treatment of severe congestive heart failure.     

Acute inotropic stimulation with dopamine in severe congestive heart failure: beneficial hemodynamic effect at rest but not during maximal exercise

Hemodynamic and metabolic effects of dopamine were studied at rest and during maximal exercise in 13 patients with severe chronic congestive heart failure (CHF). During exercise before the administration of dopamine, the stroke volume index increased from 17.1 +/- 5.2 ml/m2 at rest to 28.1 +/- 10.9 ml/m2 (p less than 0.001) at exhaustion, while pulmonary capillary wedge (PCW) pressure increased from 22.7 +/- 12.7 to 43.9 +/- 11.9 mm Hg (p less than 0.001). The arteriovenous oxygen difference increased from 8.9 +/- 2.3 ml/100 ml to 12.4 +/- 2.0 ml/100 ml (p less than 0.001) and oxygen uptake increased from 3.5 +/- 0.6 0.6 to 11.9 +/- 2.5 ml/kg/min (p less than 0.001). At rest, dopamine increased the stroke volume index to 23.3 +/- 8.1 ml/m2 (p less than 0.001) and reduced the PCW pressure to 20.5 +/- 1.1 mm Hg (p less than 0.05). However, during maximal exercise, the stroke volume index and PCW pressure were not changed by dopamine: 28.1 +/- 10.9 versus 28.6 +/- 10.2 ml/m2 (difference not significant [NS]) and 43.9 +/- 11.9 versus 42.5 +/- 11.2 mm Hg (NS), respectively. In contrast, the maximal heart rate achieved during exercise was significantly higher with dopamine, 140.3 +/- 29.3 versus 136.0 +/- 29.7 beats/min (p less than 0.05), which contributed to a slight augmentation in the maximal cardiac index, 3.82 +/- 1.13 versus 3.64 +/- 1.17 liters/min/m2 (p less than 0.05). Nonetheless, neither peak arteriovenous oxygen difference nor maximal oxygen uptake were significantly changed by dopamine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of captopril in patients with severe chronic heart failure

The hemodynamic effects of captopril (SQ 14225), an oral inhibitor of angiotensin-converting enzyme, were measured in 10 patients with severe chronic heart failure poorly controlled by digitalis and diuretics. After administration of a 25 mg dose, the cardiac index increased from 1.82 ± 0.14 to 2.28 ± 0.30 liters/min/m² (p < 0.05) while pulmonary capillary wedge pressure decreased from 22.7 ± 2.0 to 14.7 ± 4.7 mm Hg (p < 0.05). Mean blood pressure and systemic vascular resistance decreased from 85.7 ± 6.7 to 71.2 ± 12.0 mm Hg (p < 0.001) and from 1,909 ± 246 to 1,362 ± 347 dynes-s-cm⁵ (p < 0.001), respectively. Heart rate did not change significantly. There was an inverse relation between maximal augmentation in cardiac index and maximal reduction in pulmonary capillary wedge pressure (r = ?0.82, p < 0.01). While most patients demonstrated a constant hemodynamic benefit after repeated administration of captopril, some exhibited a triphasic response with attenuation of effects after the second dose and restoration of effects after the third dose. These hemodynamic benefits were observed in patients with stable chronic heart failure whose plasma renin activity was within normal range (1.1 to 7.3 ng/ml/hour).     

Hypothesis: Is congestive cardiomyopathy caused by a hyperreactive myocardial microcirculation (Microvascular spasm)?

In most congested, dilated cardiomyopathies, pathologic analysis reveals focal myocardial necrosis, microscopic scarring, interstitial fibrosis, and myocellular hypertrophy. The focal nature of these processes indicates that the cardiomyopathies may not be due to diffuse abnormalities of cardiac muscle cells, at least in the early stages, but that the changes may represent focal events affecting discrete, small volumes of tissue. Experimental evidence of microvascular hyperreactivlty (spasm), both In the hereditary cardiomyopathy of the Syrian hamster and in the acquired cardiomyopathy of the hypertensive-diabetic rat, suggests that transient spasm of the myocardial microcirculation may lead to focal myocellular necrosis and scarring, which then causes the unaffected myocardial cells to undergo compensatory hypertrophy in order to normalize the increased load per unit of myocardium. When enough myocardium is lost and the compensatory hypertrophy results in decreased contractility, congestive heart failure ensues as a systemic response to altered ventricular function. The efficacy of verapamil therapy in the Syrian hamster in preventing microvascular spasm, cell necrosis, and the subsequent development of a cardiomyopathy has provided hope that similar preventive treatment can be applied to patients with early stages of cardiomyopathy.     

Long-term therapy with a new cardiotonic agent, WIN 47203: drug-dependent improvement in cardiac performance and progression of the underlying disease

Seven patients with severe chronic congestive heart failure were treated with a new cardiotonic agent, WIN 47203 (an analog of amrinone), for an average of 7.4 weeks (range 2 to 15). At the initiation of therapy, hemodynamic improvement occurred in all patients as the cardiac index increased from 1.79 +/- 0.39 to 2.30 +/- 0.44 liters/min per m2 (probability [p] less than 0.05) and pulmonary capillary wedge pressure decreased from 24.1 +/- 6.7 to 16.1 +/- 7.8 mm Hg (p less than 0.05). Long-term therapy produced a substantial symptomatic improvement in five of the seven patients. This improvement was fully sustained in two patients and the remaining three experienced a partial return of their symptoms even though the initial hemodynamic improvements at rest remained evident in all seven patients. Withdrawal of WIN 47203 precipitated hemodynamic deterioration in all patients. The cardiac index decreased from 2.25 +/- 0.40 to 1.64 +/- 0.46 liters/min per m2 (p less than 0.05) while the pulmonary capillary wedge pressure increased from 17.1 +/- 7.8 to 23.2 +/- 12.0 mm Hg (p less than 0.05). Stroke volume index after withdrawal was lower than the control level before therapy (17.0 +/- 6.6 versus 20.3 +/- 4.7 ml/m2; p less than 0.05) and pulmonary capillary wedge pressure was similar. During long-term therapy, no undesirable side effects or hematologic changes were observed. Thus, drug-dependent hemodynamic benefits and apparent progression of the underlying cardiac disease were demonstrated during long-term therapy with WIN 47203.     

Thallium-201 accumulation during reperfusion of ischemic myocardium: dependence on regional blood flow rather than viability

These experiments in dogs were designed to determine whether the use of thallium 201 (TI-201) accumulation in patients during the reperfusion phase after streptokinase lysis of an intracoronary thrombus is a function of coronary blood flow or a function of myocardial viability. The left anterior descending coronary artery was occluded for 60 minutes in open-chest dogs, and the immediate TI-201 accumulation and regional blood flow (MBF) using microspheres was measured in 2 groups: 10 minutes after reperfusion in 9 dogs (group A) and 24 hours after reperfusion in 6 dogs (group B). There was an 80% or greater reduction in MBF in the subendocardium during ischemia in both groups of dogs, and it was inferred that the subendocardium was destined to become necrotic in group A and had become necrotic in group B dogs. The ratio of TI-201 accumulation to MBF in the tissue that had been ischemic was not significantly different from the ratio in normal tissue despite MBF being in the normal range in group A (n = 7, 2 dogs excluded because of reactive hyperemia) and being markedly decreased in group B. Thus, the immediate TI-201 distribution was related to MBF, and caution is recommended in its use to assess myocardial salvage in the early reperfusion phase after streptokinase lysis of intracoronary thrombi. These data suggest that the intramyocardial accumulation of TI-201 is predominantly a passive process and independent of Na-K ATPase.     

Effects of heart rate on experimentally produced mitral regurgitation in dogs

The effects of increasing heart rate (HR) on the hemodynamics of acute mitral regurgitation (MR) were studied in 8 open-chest dogs. Filling volume, regurgitant volume and stroke volume were calculated from electromagnetic probe measurements of mitral and aortic flows. The left atrial-left ventricular systolic pressure gradient was measured with micromanometers. The calculated effective mitral regurgitant orifice area varied from 10 to 128 mm², with a consequent regurgitant fraction (regurgitant volume/filling volume) of 24 to 62%. After crushing the sinus node, HR was increased stepwise from 90 to 180 beats/min by atrial pacing while maintaining aortic pressure constant. With increasing HR, filling volume, stroke volume, regurgitant volume and regurgitant time decreased; total cardiac output, forward cardiac output, regurgitant output, systolic pressure gradient, regurgitant fraction and the regurgitant orifice did not change; left ventricular end-diastolic pressure decreased; and left atrial v-wave amplitude increased. These results indicate that in acute experimental MR with a wide spectrum of incompetence, the relative distribution of forward and regurgitant flows did not change with large increases in HR. At rates >150 beats/min the atrial contraction occurs early and increases the amplitude of the left atrial v wave. This may contribute to the severity of pulmonary congestion in patients with MR.     

Cardiovascular consequences of primary antihypertensive therapy with prazosin hydrochloride

Ten patients with essential hypertension who had no end-organ damage were treated with prazosin, starting with a dose of 1 mg/day. The dose was titrated to a maximal tolerated dose not exceeding 20 mg/day in divided doses or until diastolic blood pressure decreased to 90 mm Hg or lower. Among this study population a statistically significant decrease in blood pressures was achieved in the supine, sitting and standing positions. Baseline studies were repeated after 8 weeks of continuous therapy. There was no significant change in peripheral plasma renin activity, serum aldosterone or urinary sodium excretion. Plasma volume increased significantly and the patient weight increased proportionately. Cardiac ejection fraction at rest did not change significantly after prazosin therapy. Exercise ejection fraction also was not changed significantly from baseline during therapy, and the exercise-induced increase in blood pressure was significantly blunted. No adverse effects of prazosin on cardiac function were detected in this short-term study.     

Mechanisms of beneficial effects of vasodilators and inotropic stimulation in the experimental failing ischemic heart

Both vasodilator and inotropic agents improve cardiac function in ischemic heart failure. However, since vasodilators may reduce coronary perfusion pressure and inotropic interventions may increase myocardial oxygen consumption (MVO₂), both may increase myocardial ischemia. Accordingly, we determined myocardial blood flow and MVO₂ in a canine model of failure induced by propranolol and volume load combined with acute coronary ligation. Both nitroprusslde and digitalis reduced ventricular diastollc pressure (LVDP) and increased myocardial blood flow in the ischemic subendocardium. Decreased systolic wall tension also caused a significant reduction in MVO₂. The benefit of nitroprusside in falling hearts was obtained even with the addition of critical obstruction of the main left coronary artery (LCA). The role of preload reduction is emphasized by the contrasting results with nitroprusside in hearts with low LVDP: (1) decreased myocardlal blood flow in ischemic subendocardium, and (2) left ventricular decompensation in animals with critical LCA obstruction. Thus, reduction of LVDP, which decreases subendocardial ischemia, is essential for the beneficial effects of vasodilators and inotropic interventions in ischemic heart failure. Decreased MVO₂ caused by reduced heart size may also have a salutary role.     

Lorcainide therapy for the high-risk patient post myocardial infarction

Nonsustained ventricular tachycardia (VT) in the late period (7 to 21 days) after myocardial infarction (MI) is reported to be a predictor of sudden death. Patients with 3-beat VT on Holter monitoring in the late infarction period would be suspected to demonstrate electrical instability on electrophysiologic studies. Forty-seven patients were identified as having at least 3-beat VT on Holter monitoring. Eighteen patients refused electrophysiologic studies or were not referred. Eight patients died; 3 were sudden deaths in 13 +/- 5 months, a 17% incidence. Twenty-nine patients underwent invasive electrophysiologic studies and 28 had inducible VT, 18 sustained and 10 nonsustained. Lorcainide prevented VT induction in 21 of the 28 patients, whereas 12 of the 22 patients studied on procainamide were protected. Lidocaine, tested in 21 patients, prevented VT induction in only 5. Lorcainide and procainamide prolonged refractoriness in those patients protected at programmed electrical stimulation (PES), whereas the QT interval was prolonged in patients in whom VT could still be induced. Twenty-seven of the 28 patients were placed on drugs predicted to be effective by PES studies, 19 on lorcainide. After a mean follow-up of 12.5 +/- 4 months the patient with noninducible arrhythmia is alive and 26 of the 28 patients with inducible arrhythmia are alive and well. Two patients died, 1 of stroke and 1 of pump failure after a second MI. No sudden deaths were observed in this group. Two patients had breakthrough arrhythmias and were treated by alternative antiarrhythmic therapy that was also effective on initial electrophysiologic studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Application of transesophageal echocardiography to continuous intraoperative monitoring of left ventricular performance

Transesophageal M mode echocardiography was used for continuous monitoring of left ventricular dimensions in 21 patients (11 with valvular and 10 with coronary heart disease) undergoing open heart surgery. Echocardiograms were recorded in six stages of the procedure and simultaneous measurements of cardiac output (with dye dilution) and atrial pressures were made. Measurements of left ventricular diameters with the transesophageal technique correlated excellently with the corresponding measurements obtained with the standard parasternal method. In patients with volume overload, surgical correction was accompanied by a decrease In diastolic dimension, velocity of circumferential fiber shortening, mid wall stress and end-diastolic stiffness, and an increase in cardiac output. Pericardial and chest wall closures generally caused a significant decrease in cardiac output, and correlated with a decrease In diastolic diameter and an increase in the stiffness constant of the left ventricle. Thus, the decrease in cardiac output may have been due to decreased distensibility of the ventricular cavity secondary to mechanical restriction by the pericardium and chest wall. Pericardial opening caused a significant delay in septal motion that was reversed by closing the pericardium. This study confirms the validity of transesophageal echocardiography and its usefulness in monitoring changes in ventricular function during cardiac surgery.     

Beneficial effect of amrinone on myocardial oxygen consumption during acute left ventricular failure in dogs

In 11 dogs ischemic left ventricular failure characterized by a 30 percent reduction In cardiac output and a left ventricular end-dlastolic pressure of 18 mm Hg or more was produced by proximal occlusion of the left anterior descending coronary artery followed by serial occlusions of the distal left circumflex coronary artery. Administration of amrlnone In an Intravenous bolus injection followed by a constant Infusion produced Improvements in cardiac output (from 1.62 ± 0.50 to 2.19 ± 0.52 Itters/min [mean ± standarddeviation], p <0.05), left ventricular end-dlastolic pressure (from 21.6 ± 3.5 to 11.0 ± 5.4 mm Hg, p <0.05) and peak positive rate of rise of left ventricular pressure [dP/dt](from 1,264 ± 241 to 1,800 ± 458 mm Hg·^?1, p <0.05). These Improvements were maintained throughout the 20 minute period of therapy. No significant alteration in heart rate or arterial pressure was noted. In parallel with the hemodynamic improvement myocardial oxygen consumption improved to 0.094 ± 0.05 and 0.092 ± 0.04 vol·^?1?^?1 after 2 and 20 minutes; respectively, of amrinone compared with 0.124 ± 0.05 during left ventricular failure (both <0.05). The effects of amrinone on left ventricular failure are due to augmented contractility and mild systemic vasodllatation. The reduction in myocardial oxygen consumption during amrlnone-treated left ventricular failure presumably results from a reduction in ventricular wall tension that more than offsets the effect of an Increase in contractility.     

Smooth muscle contraction bands in the media of coronary arteries: A postmortem marker of antemortem coronary spasm?

To date, no unequivocal morphologic markers have been described that would allow the diagnosis of coronary artery spasm to be made at autopsy. The coronary arteries of 63 adult patients without myocardial infarction were examined at autopsy, and the presence of medial smooth muscle contraction bands in these vessels was correlated with other vascular changes, myocardial pathologic changes and clinical history. These contraction bands have not been reported previously in human coronary arteries, but they were identified in experimental vascular spasm induced with catecholamines. It was found that 47 of the 63 cases were positive for contraction bands. As evidence of an antemortem process, there was a significant correlation between these changes and the presence of nonocclusive microthrombi, found in 25 cases. Contraction bands were also highly correlated with atherosclerotic plaque ruptures and mural plaque hemorrhages, which may be secondary to coronary spasm. In 78.7% of the cases positive for contraction bands, the cause of death was related to a diagnosis possibly associated with high catecholamine levels. On the basis of experimental evidence and the correlations identified in this study, coronary artery medial smooth muscle contraction bands may represent a postmortem marker of antemortem coronary spasm.     

Antiarrhythmic action of bethanidine

Studies were performed in 20 patients with symptomatic ventricular tachycardia (VT) to determine the efficacy of bethanidine compared with procainamide in preventing VT induced by programmed electrical stimulation. Before administering bethanidine, 5 to 10 mg/kg, the patients received 15 mg of protriptyline orally 24 and 2 hours before electrophysiologic studies to prevent the orthostatic hypotensive effects of bethanidine. Sustained VT (VT not spontaneously stopping) was induced in 8 and nonsustained VT (10 beats or more, terminating spontaneously) was induced in 4 patients. Bethanidine, 5 mg/kg, protected in 7 patients, and 10 mg/kg protected 1 additional patient. Procainamide, 1,000 and 1,500 mg intravenously, protected 8 of 16 patients. Bethanidine prevented VT induction in 50% of the patients not protected by procainamide. Bethanidine facilitated VT induction in 3 patients, while procainamide facilitated VT induction in 1 patient. Four patients with symptomatic VT have received bethanidine therapy for an average of 11 +/- 1.3 months, without clinical recurrence of their VT. Concomitant administration of protriptyline attenuated the acute hemodynamic changes caused by bethanidine and chronic combined therapy of protriptyline and bethanidine abolished the severe orthostatic changes in blood pressure caused by bethanidine. These studies show that bethanidine is effective in preventing VT induction and, thus, its use may not be restricted only to cases of primary ventricular fibrillation.     

Evaluation of lorcainide in patients with symptomatic ventricular tachycardia

One hundred patients with inducible ventricular tachycardia (VT) on electrophysiologic studies underwent serial drug testing with procainamide, lidocaine and lorcainide to determine comparative efficacy. Acute intravenous administration was followed by repeat programmed electrical stimulation (PES) studies on separate days for each antiarrhythmic agent. Lorcainide prevented VT induction in 69% of the 100 patients studied, procainamide in 50% of the 75 patients studied and lidocaine in 30% of 53 patients. After PES and serial drug testing, 46 patients were started on lorcainide, 9 on procainamide and 45 on other antiarrhythmic drug regimens. Eighty percent of the patients have remained on lorcainide therapy, whereas 47% have continued on other drug therapies started over 17.5-month mean follow-up period. Despite sleep-wake disturbances and a need for sedation at night, lorcainide therapy was well tolerated in this population and remained an effective antiarrhythmic agent with prolonged administration.