Wood, Earl H.

I. Tension was recorded from a segment of a thin bundle of calf or sheep ventricular fibers in which the membrane potential could be changed electrically, using a sucrose-gap technique. After reversal of membrane potential and consequent contracture for 2 to 3 seconds, a positive inotropic effect 2 to 12 times that which occurred during paired-pulse stimulation was obtained. The decay of this potentiated state was slow in resting preparations (average half-life, 95 seconds), but was determined by the number of beats in driven preparations (about eight beats to return to control amplitude). Lengthening consecutive action potentials by subthreshold constant depolarizing currents or 5-mv shifts in the membrane potential by 50-msec current pulses during the plateau phase of successive action potentials caused positive inotropic effects, attaining a steady state in about eight beats. Reversing the polarity of such currents (hyperpolarization) caused negative inotropic effects with the same phase dependency as for depolarizing currents. These negative inotropic effects attained a steady state in six to eight beats. The first action potential after cessation of these currents was close to normal, whereas return to control tension required six to eight beats. The half-life of decay of these negative inotropic states at rest was similar to that of positive inotropic states. Decay of inotropic states in contracting preparations was phase dependent, occurring only during the rapid depolarization and plateau phases of the action potential. II. These and other strength-interval effects on cardiac contractility in a constant chemical and physical environment are consistent with two hypotheses. (1) The presystolic level of intracellular calcium bound to specific (rapid release) sites on the sarcoplasmic reticulum, the inner surfaces of the sarcolemma and T tubules, is a major determinant of the level of [Ca 2+ ] 1 attained during the initial phase of an action potential and hence the tension developed by mammalian cardiac muscle (that is, its inotropic state) at that particular instant. (2) The amount of intracellular calcium present at these sites at any instant after an action potential (that is, the moment-to-moment inotropic state of the muscle) is predetermined in the inverse direction of the intersystolic intervals of prior systoles and in the positive direction by the duration and magnitude of the plateau phases of prior action potentials and (for rest periods as long as 10 seconds) the elapsed time, in an exponentially decreasing fashion, since termination of the last absolute refractory period.

Multiple measurements of left ventricular volumes, ejection fractions, and circulatory pressures were made under conditions of varied outflow resistance in five intact anesthetized dogs by using a biplane videoangiographic recording system which displays simultaneously two roentgen images on the same television screen, records the images on video tape, and requires low radiation levels and small amounts of contrast medium. Aortic pressure was controlled by intra-aortic infusion of angiotensin or acetylcholine. With spontaneous sinus rhythm and normal aortic pressure, end-diastolic volume averaged 35 ml (2.3 ml/kg), and ejection fraction averaged 47% of end-diastolic volume. When aortic pressure was increased, average end-diastolic volumes increased to 53 ml and ejection fractions decreased to 29%. Conversely, when aortic pressure was decreased, average ejection fraction increased to 73%, although changes in stroke volume were usually not large under these conditions. Concomitant large changes in the shape of the left ventricular cavity were also observed. Similar changes were observed when heart rate was maintained constant by electrical pacing of the atria and ventricles with a constant atrial-ventricular stimulus interval. The variability in left ventricular volume and ejection fraction observed in the same animal during different circulatory states may account in part for the differences in values for these variables reported by different investigators.

Cardiac and aortic pressures were recorded after stellate ganglionectomy and vagotomy. Acute heart block was produced by injecting the atrioventricular node, and atrial and ventricular systoles were controlled electronically to occur independently or in any desired relationship. Angiocardiograms recorded on video tape after injections of 4 ml 69% Renovist into the left ventricle were analyzed with a videodensitometer able to detect small refluxes of contrast medium into the left atrium and correlate them with phases of the cardiac cycle. When ventricular driving was temporarily suspended but atrial driving continued, pressure records indicated mitral valve closure after each atrial systole, but reflux of contrast medium into the atrium occurred after each systole not followed by a normally sequenced ventricular systole. Driving with a 2: 1 atrioventricular stimulation resulted in reflux, with the alternate atrial contraction dissociated from ventricular systole. Thus, the mitral valve was not effectively closed by atrial systoles that were not followed by normally sequenced ventricular systoles.

Intrapericardial pressures were recorded via a saline-filled Teflon catheter (o. d., 1.3 mm) in 11 anesthetized dogs studied without thoracotomy. Seven animals were studied before, during, and after 1-min exposures to transverse accelerations that ranged from 1G (normal gravitational environment) to 7G when in the supine (+G j ), prone (-G x ), left decubitus (+G v ), and right decubitus (-G y ) positions. Four additional animals were studied at 1G only, while in these same body positions. Pressures also were recorded from both atria, right ventricle, aorta, esophagus, and the potential pleural space. Mean end-expiratory intrapericardial pressure varied directly with the vertical height of the recording site in the thorax during all conditions studied, as would be expected in a hydrostatic system. Transpericardial pressures were not significantly different from zero at all levels of acceleration studied. Transmural left and right atrial pressures were independent of the height of the recording site in the thorax and were unchanged during exposures to transverse accelerations that ranged from plus to minus 7G x .

Pressures at multiple sites in the thorax of supine anesthetized dogs were recorded simultaneously with fluid-filled catheters inserted percutaneously. Pleural and pericardial pressures were corrected to the level of their respective recording catheter tips as determined by roentgenograms. Intracardiac pressures were referred to the midthoracic coronal plane or to the vertical level of the pericardial catheter tip. Pericardial pressures at end-expiration averaged -5.0 cm H 2 O (range 0 to - 13) and varied with the vertical position of the catheter tip, becoming less negative as the height above the midthoracic coronal plane diminished. Acute right heart failure was produced by partial obstruction of the pulmonary artery by a catheter-tip balloon. Although mean right atrial pressure increased by an average of 26 cm H 2 O, consistent increases in pericardial pressure did not occur. Similarly, during acute obstruction to left ventricular outflow by inflation of a balloon within the thoracic aorta, left atrial end-diastolic pressure increased by an average of 14.5 cm H 2 O, but no consistent increase in pericardial pressure was recorded. No systematic changes in pleural pressure were detected in either case. Thus there was no evidence of pericardial restriction of cardiac dilatation during acute heart failure under these experimental conditions.

In dogs studied without thoracotomy, under morphine-pentobarbital anesthesia and with an average heart rate of 71 beats/minute, atrial systole contributes to ventricular function to a small but significant degree. Stroke volume increased by 7 to 8% when atrial systole was timed to occur 0.1 second prior to closure of the atrioventricular valves, and decreased a similar magnitude when the contribution of atrial systole to ventricular filling was rendered ineffective by the use of an A-V delay of zero so that atrial emptying into the ventricles was prevented by the closed A-V valves. Increases or decreases in right atrial pressure of several centimeters of water induced by infusion of 6% dextran and by hemorrhage, respectively, were not associated with demonstrably significant alterations in these effects.

1. Indicator dilution curves (concentration versus time) were recorded from the femoral and dorsalis pedis arteries of normal men after injections of indocyanine green into the superior vena cava or thoracic aorta. A four-parameter mathematical model, the lagged normal density curve, adequately described the form of the portion of these curves representing indicator passing by the sampling site for the first time. 2. The curves were observed to be of constant shape, the spread of the curve being approximately linearly related to the mean transit time t. The spread was dependent on the injection site; dispersion was shown to be greatest in the central circulation, less in the aorta, and still less in the arteries of the leg. For the latter segment, the mean transit time t. The spread was dependent 0.3 t, the square root of the variance was 0.18 t, and the parameters of the lagged normal density curve, σ and τ, were 0.09 t and 0.16 t, respectively. 3. The linear relationships between parameters of the recorded curves and the mean transit times indicate that the effect of rate of flow, over a range from resting values to four to six times above resting values, has almost no influence on the dispersion. This suggests that the flow characteristics are essentially unchanged over this range. Such linear relationships always occur with laminar flow but cannot prove its existence because turbulent flow can also produce this result. The similarity of the linear relationships at low flow rates to those at high flow rates, where turbulence almost certainly is present, suggests that arterial flow is usually turbulent. Turbulence may be expected at relatively low flow rates in nonhomogeneous fluids driven by a pulsatile head of pressure through elastic, branched, tapering, curved tubes.

The constant-rate-injection, indicator-dilution technic was used to determine thoracic aortic blood flow before, during, and after five minutes of single-leg exercise (bicycle ergometer) in five healthy male subjects in the supine position. Resistance to blood flow in the lower body and mean aortic pressure decreased immediately at the onset of exercise, at the same time that thoracic aortic blood flow and heart rate increased. There was a further slow rise of heart rate, mean aortic pressure, and thoracic aortic blood flow along with a decrease of lower body resistance until fairly stable levels were reached after five minutes of exercise. After five and ten minutes' rest all values tended to return toward those observed in the control state. These data are consistent with the concept that baroreceptor activity may play an important part in the early cardiovascular responses to exercise in man. Most of the cardiovascular response to this exercise occurred in the first 30 seconds.

The distances between the aortic valve and sites in the aorta from which no retrograde flow of injected indicator could be detected in the left ventricle were determined, without thoracotomy, in two normal dogs and in ten dogs with chronic experimental aortic regurgitation. It was found that these distances attained maximal values when the aortic injections were timed to occur just at the end of systole or onset of diastole. Distances downstream from the origin of the left subclavian artery from which no retrograde flow occurred to this vessel were determined similarly in these same animals and, in confirmation of Warner and Toronto, similar relationships to the timing of the injections were obtained. These distances down the aorta, designated as "disappearance distances", were converted to "disappearance volumes" by measuring the diameters of the silhouette of successive aortic segments from aortograms made after contrast medium was injected into the left ventricle of these animals. The regurgitant flow through the aortic valve per heartbeat was estimated on the basis of the amount of immediately appearing indicator detected in the left ventricle following injection of indicator approximately 1 cm downstream from the aortic valve. Correlation coefficients of 0.88 and 0.77 were obtained between these stroke-regurgitation values and the disappearance volumes from the aortic valve and subclavian artery, respectively. The standard errors of the estimate of the regurgitant flow per beat from these regression equations were ± 2.7 and ± 2.9 ml/beat, respectively. The correlation coefficients between stroke-regurgitation values and the disappearance distances from the valve and subclavian artery were 0.83 and 0.81, respectively, and the respective standard errors of the estimate of stroke regurgitation from these regression equations were ± 3.2 and ± 3.3 ml/beat. It is concluded that determination of the maximal distances downstream in the aorta of sites from which retrograde flow of injected indicator can be detected in the left ventricle or subclavian artery is a valid method for estimating the severity of experimental aortic regurgitation in dogs. Since determinations of the disappearance distance from the aortic valve can be carried out readily in conjunction with measurement of the left ventricular regurgitation fraction, it is suggested that advantage be taken of the increase in reliability which accrues from the combined use of these two independent methods for the estimation of the degree of aortic regurgitation.

The square-wave electromagnetic flowmeter was used to assess the upstream sampling dye-dilution technic for quantitating aortic regurgitation by simultaneous determinations of the regurgitant fraction by flowmeter, as given by the ratio of regurgitant volume to total stroke volume (RV/TSV) and the identical ratio of regurgitant flow to total forward flow (Q R /Q F ), and the regurgitant fraction by dye curve, as given by the ratio of the areas of the immediately appearing portion of the left ventricular curve to the area of the femoral artery dye curve (LV A /FA A ), after injection of indicator approximately 1 cm downstream to the aortic valve. A good correlation (r = 0.91) was found between these two independent methods which can be represented by the regression equation Q R /Q F = 0.82 (LV A /FA A ). This correlation indicates that the concept that the regurgitant fraction of indicator (LV A /FA A ) is proportionate to the regurgitant fraction of blood (RV/TSV) is valid. The observed systematic difference between flow-meter and dye-curve regurgitant fractions may be due to the fact that time-average rather than volume-average concentrations of the indicator are obtained by sampling of blood through eatheters. Two different and independent calibration technics were used to establish a calibration factor for converting recorded flowmeter deflections to volumetric units for measurement of rates and volumes of blood flow in the ascending aorta. The first technic involved simultaneous recording of dye-dilution curves and velocity pulses in the ascending aorta by the flowmeter before the production of aortic regurgitation. The second involved bidirectional perfusion of the isolated aorta at known rates of blood flow with simultaneous flowmeter recordings at the termination of each experiment. The data obtained validated the use of the flowmeter for measurements of total stroke volume and regurgitant stroke volume. The close correspondence between flowmeter recordings of the regurgitant flow and hydraulic estimates of regurgitant flow, based on the size of the defect in the aortic valve measured at necropsy and continuous records of the pressure gradient across the valve, also lent strong support to the validity of these measurements. The relationship Q R = Q S (Q R /Q F )/(1 - Q R /Q F ) can be used to estimate regurgitant flow from values of the regurgitant fraction (Q R /Q F ) and the systemic flow (Q S ). The mathematical relationship of the regurgitant fraction to regurgitant flow, determined by the dilution-curve technic, plus the variability obtained between simultaneous flowmeter and dilution-curve estimates of regurgitation, indicate that the error in the estimation of regurgitant flow by the dye-dilution technic is least for small-to-moderate degrees of regurgitation and increases progressively with the severe degrees of regurgitation associated with regurgitant fractions of greater than 0.6. On the basis of 231 simultaneous determinations by the indicator-dilution and flowmeter technics carried out in nine dogs, and assuming that the flowmeter values were uniformly correct, it was estimated that the standard deviation of the errors in measurement of regurgitant flow by the upstream sampling dye-dilution method in these experiments was 0.15 L per minute for regurgitant fractions below 0.6. and that this variability increased so that the standard deviation was 1.3 L per minute at regurgitant fraction levels of 0.9 to 1.0. The results of determinations carried out over a range of heart rates from 39 to 216 beats per minute indicate that the indicator-dilution method is applicable over a wide range of heart rates. The observed changes in aortic regurgitation with variation in heart rate correlated closely with the changes estimated by hydraulic equations based on the hydrodynamics of steady flow through an orifice. The increase in regurgitant stroke volume with increased duration of diastole at slow heart rates was disproportionately greater than the increase in total stroke volume, so that the effective forward (systemic) flow fell to extremely low levels at slow heart rates, particularly in dogs with large defects in the aortic valve. The applicability of the upstream sampling indicator-dilution technic to the detection and estimation of the severity of aortic regurgitation in human beings merits further study.