William W. Parmley

Hemodynamic and Metabolic Responses to Vasodilator Therapy in Acute Myocardial Infarction

Hemodynamic effects of vasodilator therapy (phentolamine or nitroprusside) were studied in 38 patients with acute myocardial infarction (AMI). Cardiac metabolism was studied in 19 of the 38 patients. According to the initial level of left ventricular filling pressure (LVFP) and left ventricular stroke work index (SWI), patients were divided into three groups: Group I-nine patients with LVFP 15 mm Hg or less; Group II-14 patients with LVFP > 15 mm Hg and SWI >20 g-m/m2; Group III-15 patients with LVFP > 15 mm Hg and SWI < 20 g-m/ m2. In Group I most patients were clinically uncomplicated. In Group IL most patients had clinical left ventricular failure including one patient who had clinical features of cardiogenic shock. Group III patients all had severe left ventricular failure, with eight patients in clinical shock.In all groups LVFP, pulmonary artery pressure, right atrial pressure, and systemic and pulmonary vascular resistance decreased significantly with vasodilator therapy with only a slight to moderate decrease in arterial pressure. In Group I patients SVI decreased (-7%) together with an increase in heart rate. Significant improvement in left ventricular performance, however, was observed in Groups II and III as indicated by increased stroke volume index (SVI) and cardiac index (CI) and decreased LVFP. The increase in SVI and CI was of similar magnitude in both Group LI (SVI +18%, CI +24%) and Group III (SVI +28%, CI +29%) patients, a change suggesting that vasodilation thereby may be applicable and beneficial even in the presence of severe depression of cardiac performance.Improved left ventricular performance in group II and III patients was accompanied by a slight decrease in coronary blood flow, myocardial oxygen consumption, and transmyocardial oxygen extraction. There was no change in myocardial lactate metabolism in any group. In vitro studies in isolated cat papillary muscle preparations showed no direct positive inotropic effect of either phentolamine or nitroprusside. Thus, significant improvement in left ventricular performance occurs during vasodilator therapy in patients with AMI and elevated LVFP, even in the presence of severe depression of cardiac performance. Furthermore, this improvement is not accompanied by increased metabolic cost. Vasodilator therapy, therefore, may have an important role in the treatment of pump failure complicating myocardial infarction.

Assessment of Passive Elastic Stiffness for Isolated Heart Muscle and the Intact Heart

A sensitive method was developed for detecting stiffness changes in the left ventricle. Stress-strain relationships (σ—ϵ) were obtained in the form dσ/dϵ = kσ + c from published studies on eight normal canine hearts, five infarcted canine hearts, and seven isolated cat papillary muscles. Utilizing pressure-volume relationships, the elastic stiffness (dσ/dϵ) and the stiffness constant (k) were also evaluated in patients with normal ventricles, inappropriate hypertrophy, and congestive cardiomyopathy. The k values were 35.0 ± 1.7 (isolated muscle, 30°C), 37.3 ± 1.9 (normal canine, 23°C), and 23.9 (infarcted). For the patient groups, k and the passive elastic stiffness were 15.8 ± 0.3 and 249 ± 22.4 g/cm2 for 13 normal patients, 26.4 ± 1.7 and 286 ± 32.0 g/cm2 for 7 patients with inappropriate hypertrophy, and 20.1 ± 1.2 and 1360 ± 209 g/cm2 for 6 patients with congestive cardiomyopathy. The results indicate that (1) k is sensitive to stiffness changes due to infarction, (2) hypertrophy causes an increase in the value of k although elastic stiffness remains within normal limits, and (3) k for the intact human heart is lower than it is for isolated muscle.

Dlastolic Pressure-Volume Relationship in the Canine Left Ventricle

Analysis of the passive pressure-volume filling curve of the left ventricle demonstrates that heart size and ventricular geometry exert major effects on the pressure-volume curve in the absence of changes in intrinsic muscle stiffness. Because the pressure-volume relationship is curvilinear, both quantitative and qualitative comparison of pressure-volume curves from different hearts is difficult. In the fresh isolated canine left ventricle, the pressure-volume relation was found to be almost perfectly exponential throughout a range of filling pressures from 5 to 30 mm Hg. Therefore, a precise linear and quantitative expression of the pressure-volume relation (dP/dV=aP+b) was developed (r=0.995). The effect of isolated changes in either initial ventricular volume (mean σa=3.1%) or ventricular geometry (mean σa=27.1%) upon the slope, or a constant of this function was small in comparison to changes induced by rigor mortis (mean σa =45%). It was concluded that the a constant was primarily affected by changes in left ventricular wall stiffness. In this manner, comparison of the pressure-volume relationship from different hearts is possible, and the contribution of changes in wall stiffness may be quantified.

Serum Cortisol, Plasma Free Fatty Acids, and Urinary Catecholamines as Indicators of Complications in Acute Myocardial Infarction

Levels of serum cortisol, plasma free fatty acids (FFA), and urinary catecholamines were collected in 31 patients with acute myocardial infarction on the day of admission to the coronary care unit (samples obtained from 15 patients with diseases other than myocardial infarction were considered as controls). These values were correlated with the presence or subsequent development of left ventricular failure, arrhythmias, shock, or death. Sixteen of 17 infarction patients without the above complications had cortisol levels less than 20 μg%; 10 of 12 patients with complications had higher cortisol levels. All of the infarction patients without complications had plasma FFA levels less than 1100 μEq/liter, while six of nine patients with complications had levels of 1100 μEq/liter or higher. Fourteen of 16 patients without complications had urinary catecholamines less than 12.5 μg%, while seven of 10 patients with complications had levels greater than this. Of interest were a few patients without complications on admission, but with elevated cortisol or FFA levels, who developed complications on the following day. The results of the present study suggest that the generalized metabolic stress of acute myocardial infarction results in elevations of cortisol, FFA, and catecholamines as measurable biochemical indicators and/or predictors of the severity of the infarction.

Effect of sotalol on clinical arrhythmias

Abstract Sotalol (MJ 1999) was administered to 20 patients for the treatment of 22 episodes of supraventricular and 6 episodes of ventricular arrhythmias. The dose range was 9 to 50 mg intravenously and 20 to 80 mg orally given every 6 hours. In 4 of 6 patients supraventricular tachycardia was converted to normal sinus rhythm. In 4 with episodic supraventricular tachycardia, Sotalol prevented further recurrences in all. In 1 patient atrial flutter was converted to normal sinus rhythm. In 3 others with atrial flutter, and in 3 with atrial fibrillation, Sotalol slowed the ventricular response from an average rate of 125 to 72 beats/min. In 1 patient with episodic atrial fibrillation and another with episodic ventricular tachycardia, Sotalol prevented further recurrences. In 1 of 2 patients Sotalol decreased the frequency of premature atrial contractions; in 5 patients with premature ventricular contractions, it abolished them in 2 and reduced their frequency in the other 3. Side effects included transient hypotension in 3 patients and bradycardia sufficient to require reducing the dose of Sotalol in 4. It is concluded that Sotalol is a moderately effective antiarrhythmic drug which may be preferable to other beta adrenergic blocking agents because of its lack of substantial myocardial depressant effects.

Relation of Vmax to Different Models of Cardiac Muscle

The present study was undertaken to reevaluate the effects of preload on maximum velocity of shortening at zero load, Vmax, relative to the length-tension curve. Force-velocity relations were measured from afterloaded isotonic contractions and were calculated from isometric contractions of isolated cat papillary muscles. Results were interpreted in the light of three alternative mechanical models of muscle. Vmax was obtained by mathematical extrapolation of each force-velocity relation to zero load using a hyperbolic least-squares analysis performed on an IBM 360 computer. With the application of all three muscle models to isotonic force-velocity relations, Vmax was relatively constant at low preloads but was reduced substantially as muscle length approached Lmax (the length at the peak of the active length-tension curve). In force-velocity relations from isometric contractions, similar results were obtained with the two-element and Voigt models of muscle. With the Maxwell model, Vmax remained more nearly constant near Lmax. Peak developed force (isometric contraction), maximum dP/dt, peak calculated velocity of the contractile element (VCE), and Vmax were compared in terms of their dependence on preload and length over the entire length-tension curve (using the Maxwell model). Peak VCE and Vmax were similar and were less dependent on preload than maximum dP/dt or developed force.

Plasma cyclic adenosine 3′5′-monophosphate (AMP) levels in acute myocardial infarction☆

Abstract Plasma cyclic adenosine 3′5′-monophosphate (AMP) levels were measured in 44 patients with acute myocardial infarction, 33 patients with other cardiac and noncardiac diseases and 20 normal volunteers. The normal range of cyclic AMP was 4 to 16 picomoles/ml. The 35 surviving patients with acute myocardial infarction tended to have a slightly increased level of plasma cyclic AMP during the first 24 hours with a subsequent return to normal; the 9 nonsurvivors had abnormally high levels of cyclic AMP. An inverse correlation was found between cyclic AMP levels and stroke work index, and plasma cyclic AMP levels were of equal or better prognostic value than stroke work index. Plasma cyclic AMP levels were in the normal range in patients without acute myocardial infarction. Thus, very high levels of plasma cyclic AMP, found in patients with fatal myocardial infarction, appear to have clinical significance.

Dissociation of myocardial contractility and pump performance in hemorrhagic shock. Correlation of in vivo measurements with assay of shock plasma in papillary muscle.

Myocardial performance and contractility were evaluated during standardized hemorrhagic shock in dogs and cats. Myocardial contractility, measured by utilizing Vmaχ from the isovolumic force-velocity relation, was maintained despite a decline in cardiac performance and progression to irreversible shock. By contrast, in animals subject to β-adrenergic blockade, there was a significant decline of myocardial contractility, suggesting dependence of V on sympathetic neurohumoral support during shock. Plasma taken at hourly intervals from dogs in shock was assayed for inotropic effect utilizing a cat papillary muscle preparation. Fresh plasma taken during shock caused a small augmentation of contractility, while plasma taken at the same time, but frozen before assay, was depressant. It is concluded that in severe and irreversible hemorrhagic shock there is a dissociation between ventricular function as measured by cardiac output and filling pressure, and contractility as measured by Vmaχ. This preservation of Vmaχ is probably related to stimulating factors in shock plasma, such as the catecholamines, which overshadow the presence of any myocardial depressant factors.

Effects of D- and DL-propranolol on myocardial adenyl cyclase activity.

Summary The direct effects of d- and dl-propranolol (Inderal) on myocardial adenyl cyclase activity were determined on in vitro preparations from cats and guinea pigs. In both species, dl-propranolol depressed myocardial adenyl cyclase activity at all dose levels greater than 10-8 M. The pure dextroisomer produced less depression of the adenyl cyclase activity. In preparations from reserpinized cats, d-propranolol had no effect on myocardial adenyl cyclase activity up to 10-4 M, while the effects of dl-propranolol were slightly reduced. Since d- and dl-propranolol have identical depressive effects on myocardial contractile force, the present data demonstrate a dissociation between their effects on adenyl cyclase activity and force development.

Diminished Responsiveness of the Failing Human Myocardium to Glucagon

Eight left ventricular papillary muscles were removed from patients at the time of mitral valve replacement (all patients functional class 3 to 4) and were studied in a myograph in vitro</