Effects of Pericardial Constraint on Left Ventricular Mechanoreceptor Activity in Cats
Background The purpose of this study was to assess the effect of pericardial constraint on the activity of left ventricular (LV) mechanoreceptors with nonmyelinated vagal afferents.
Methods and Results Single-unit activity of cervical vagal afferents (conduction velocity, 1.6±0.5 m/s) was recorded in six cats anesthetized with α-chloralose. Discharge frequency during diastole (DFdiastole) and systole (DFsystole) was determined after correction for conduction delay of the nerve action potential. When the pericardium was closed and LV end-diastolic pressure (LVEDP) was ≈5 mm Hg, DFdiastole and DFsystole were 1.3±1.0 and 0.3±0.1 impulses per second, respectively. Volume expansion increased LVEDP, LV transmural LVEDP, and segment length and was associated with a significant increase in DFdiastole. At a given LVEDP, DFdiastole was significantly greater in the absence of the pericardium than with the pericardium closed. Removal of the pericardium increased the slope of the relation between DFdiastole and intracavitary LVEDP but did not alter the slope of the relations between DFdiastole and transmural LVEDP and LV segment length.
Conclusions These results suggest that, rather than the absolute value of intracavitary LVEDP, transmural LVEDP and distension appear to be more important determinants of diastolic LV mechanoreceptor activity and that pericardial constraint may attenuate mechanoreceptor activity by limiting cardiac distension.
Most known cardiac mechanoreceptors with nonmyelinated vagal afferents have been found in the LV. Activation of these receptors causes vasodilation, hypotension, and bradycardia. Previous investigations have shown that these LV mechanoreceptors can be activated by ventricular distension induced by volume expansion or outflow-tract obstruction. Although discharge of the mechanoreceptors occurs during both diastole and systole, the discharge frequency appears to correlate well with LVEDP.1 2 3 4 5 Furthermore, the increased receptor discharge rate observed when afterload is increased is seen only when LVEDP is also elevated. Thus, the change in LVEDP has been used to predict activation of the reflex response.6 7 However, LV distension is determined by transmural pressure, not by intracavitary pressure.8 9 Transmural pressure is the difference between LV intracavitary and pericardial pressures and is equal to LV intracavitary pressure after removal of the pericardium. In some circumstances, the pericardium can substantially constrain the LV, impede its distension, and thereby potentially modulate LV mechanoreceptor activity. Since most previous studies were performed in animals in which the pericardia had been opened, the effect of the pericardium on LV mechanoreceptor activity remains unknown.
Accordingly, the present study was designed to assess the effects of pericardial constraint on LV mechanoreceptor activity. Single-unit activity of cardiac vagal afferents was measured in cats. Relations between LV mechanoreceptor activity and LVEDP, transmural LVEDP, and LV segment length were determined during volume expansion. The effects of pericardial constraint were examined by comparisons of these relations before and after removal of the pericardium.
Experiments were carried out in six cats weighing 4.5±0.5 kg (mean±SD). Anesthesia was induced with sodium thiopental (25 mg/kg IV) and maintained with an initial dose of α-chloralose (30 mg/kg IV) followed by 10-mg/kg doses as required. The animals were ventilated with supplemental oxygen by a constant-volume respirator (model 607, Harvard Apparatus Co Inc) and a closed rebreathing system. Arterial Po2, Pco2, and pH were measured periodically and were maintained at 80 to 120 mm Hg, 30 to 40 mm Hg, and 7.3 to 7.4, respectively, by adjustment of the tidal volume. Body temperature was maintained at 36°C to 37°C by a warming blanket and a heating lamp.
A midline sternotomy was performed with the cats supine. The ventral surface of the pericardium was incised transversely along the base of the heart. A pair of ultrasonic crystals was implanted in the LV inferior wall for measurement of segment length with a sonomicrometer (Triton Technology). Pericardial pressure was measured with a flat liquid-containing Silastic rubber balloon transducer (internal dimensions, 1.8×1.8 cm) sutured loosely onto the anterolateral surface of the LV.10 11 After instrumentation had been completed, the pericardium was reapproximated, and care was taken not to compromise pericardial volume.10
To identify the LV mechanoreceptors, snares were placed around the ascending aorta and the pulmonary artery to manipulate pressures in the left and right sides of the heart, respectively. A balloon-tipped catheter was inserted through an incision in the left atrial appendage and positioned near the mitral valve so that LA pressure could be increased by balloon inflation. Isolation of the right cervical vagus and right cardiac nerve and sectioning of the right vagal thoracic trunk were performed according to a previously described method.4 5
LV and mean aortic pressures were measured with fluid-filled catheters introduced via the femoral arteries. End-diastolic (ie, end of the a wave) and peak-systolic LV pressure measurements were recorded. A 6F catheter connected to a pressurized bag was inserted into a femoral vein for volume infusion. All pressure and segment-length signals were conditioned (model VR 16, Electronics for Medicine/Honeywell) and recorded on a personal computer (model PC/AT, IBM). The data were subsequently analyzed with specially developed software (cvsoft, ODESSA Computer Systems Ltd).
Recording of Nerve Activity
Single-unit activity of an afferent fiber in the right cervical vagus was recorded. The nerve was placed on a black plastic dissection plate and immersed in a pool filled with mineral oil, the temperature of which was maintained between 35°C and 36°C. Thin filaments were isolated and transected centrally. The filament was placed on thin, bipolar stainless steel electrodes. The signal was recorded with a high-impedance amplifier (NL 100AK Headstage, NeuroLog System, Digitimer Ltd) and a preamplifier (NL 104A, NeuroLog System) with high- and low-frequency cutoffs set at 1000 to 3000 Hz and 30 Hz, respectively. To obtain a single active-fiber preparation, the thin filament in the right cervical vagus was dissected until one or two active units (with easily distinguishable action potentials) were identified. To ensure that these units were nonmyelinated afferent fibers, their conduction velocities were determined by electrical stimulation of the right cardiac nerve. The interval between the stimulus and the evoked potential and the distance between the stimulating and recording electrodes were used to calculate the conduction velocity. After completion of the experimental protocol, the conduction time (from the LV myocardium to the recording electrode) of the action potential was measured in the open, nonbeating heart. First, the endocardial surface was mechanically probed until an action potential was recorded in the fiber. Then that same region was stimulated electrically, the electrical stimulus and the resultant action potential were recorded, and the intervening interval was measured.4 5 Thus, the time required for an action potential to travel from the receptor to the site of recording having been directly measured, action potentials recorded from the right vagal single nerve fiber were ascertained to have originated during cardiac diastole or systole.
Nerve activity was displayed on an oscilloscope and, with LV pressure and segment length, was recorded on an analog tape recorder (3968A Instrumentation Recorder, Hewlett-Packard). Later, the data were digitized off-line at a rate of 4000 samples per second (Hz) per channel at 30-second intervals by use of special software (cvsoft). To relate the nerve activity to an appropriate phase of the cardiac cycle, temporal delays for conduction of the action potential and for the LV pressure transmission (10 ms for the LV fluid-filled catheter) were corrected by shifting both these channels forward in relation to the ECG. LV systole was defined as the period from the onset to the last one third (approximately at the time when the incisura of aortic pressure wave occurred) of the time-shifted LV systolic pressure wave. The remainder of the cardiac cycle was considered to be diastole.
Sequential brief aortic, pulmonary artery, and mitral valve occlusions were used to identify the vagal afferent fibers that originated from the LV. If afferent fibers increased activity during aortic occlusion but failed to respond to the pulmonary artery and mitral valve occlusions, they were considered to have originated from the LV. Control recordings with a closed pericardium were made when LVEDP was ≈5 mm Hg. A mixture of dextran and saline was then infused to raise LVEDP in 5 mm Hg increments to ≈25 mm Hg. Nerve activity and hemodynamic variables were recorded at each incremental level. After recordings at LVEDP ≈25 mm Hg, the pericardium was rapidly removed. After more of the dextran-saline mixture was infused to restore LVEDP to ≈25 mm Hg, recordings were repeated at each 5 mm Hg decrement in pressure induced by graded hemorrhage. Upon completion of the experiment, the heart was opened and the action-potential conduction time was determined as described above.
Relations between DFdiastole and LVEDP, transmural LVEDP, and segment length recorded with the pericardium closed were compared with those recorded after removal of the pericardium at the same levels of LVEDP (ie, ≈5, 10, 15, 20, and 25 mm Hg). Transmural LVEDP was calculated as the difference between LVEDP and pericardial pressure; transmural LVEDP was equal to LVEDP when the pericardium was absent. The significance of changes in the discharge frequency at any given level of LVEDP was determined with a Student’s paired t test. Changes in the relations of DFdiastole to transmural LVEDP and segment length were compared before and after removal of the pericardium by two-way ANOVA with a repeated-measures design. All data are expressed as mean±SD. Values of P<.05 were considered to be significant.
Characteristics of LV Mechanoreceptors
When the pericardium was closed and when LVEDP was ≈5 mm Hg, DFdiastole and DFsystole were 1.2±0.4 and 0.3±0.1 impulses per second, respectively (Table⇓). The conduction velocity in afferent fibers was 1.6±0.5 m/s. Thus, these afferents were classified as nonmyelinated or C fibers.12 At the end of the experiment, the receptors were determined to be located in the inferior wall in four cats, the anterior wall in one, and the ventricular septum in one. The inferior and anterior receptors were in epicardial layers, whereas the septal receptor was in the LV side of the septum. The action-potential conduction time from the mechanoreceptor to the recording electrode was 245±74 ms. Fig 1⇓ illustrates the temporal relations between cardiac vagal nerve activity and LV pressure and segment length. Nerve activity and LV pressure traces were shifted to the left to compensate for conduction delays of the action potential and the catheter transmission time of the LV pressure signal.
Effects of Pericardial Constraint on LV Distension
Volume expansion increased LVEDP, pericardial pressure, transmural LVEDP, and LV end-diastolic segment length (Table⇑). Removing the pericardium caused the relation of LVEDP to segment length to be shifted to the right such that, for a given value of LVEDP, segment length was greater than when the pericardium was closed (Fig 2⇓).
Effects of Pericardial Constraint on LV Receptor Discharge
When the pericardium was closed, graded volume expansion (which increased LVEDP from ≈5 to 25 mm Hg) was associated with an increase in DFdiastole from 1.3±1.0 to 7.4±2.4 impulses per second (Table⇑ and Fig 3⇓). This volume expansion was associated with increases in DFsystole from 0.3±0.1 to 2.1±1.5 impulses per second and increases in LV systolic pressure from 81±12 to 127±15 mm Hg (Table⇑).
After removal of the pericardium, at LVEDP ≈25 mm Hg, DFdiastole increased from 7.4±2.4 to 14.6±2.1 impulses per second (P<.05 versus pericardium closed) and, at LVEDP ≈5 mm Hg, from 1.3±1.0 to 2.1±1.7 impulses per second (P=NS), whereas DFsystole was increased to 0.6±0.2 impulses per second (Table⇑). Volume expansion significantly increased the slope of the DFdiastole-LVEDP relation from 0.36±0.04 impulses per second per mm Hg when the pericardium was closed to 0.79±0.07 impulses per second per mm Hg after removal of the pericardium (P<.01, Fig 3⇑). Thus, a given increase in LVEDP was associated with a greater increase in DFdiastole in the absence of the pericardium compared with that when the pericardium was closed (P<.01, Table⇑ and Fig 3⇑). In contrast, the slopes of the relations between DFdiastole and transmural LVEDP and segment length were not altered by removal of the pericardium (Figs 4⇓ and 5⇓). After the pericardium was opened, the volume expansion that was required to restore LVEDP to ≈25 mm Hg increased DFsystole from 2.1±1.5 to 3.5±1.6 impulses per second and LV systolic pressure from 127±15 to 147±14 mm Hg (P<.05, Fig 6⇓); there were no associated changes in the slope or any shift in the relation of DFsystole to systolic pressure when the pericardium was removed.
The major finding of the present study was that the diastolic activity (DFdiastole) of LV mechanoreceptors with nonmyelinated vagal afferents was determined by transmural LVEDP and the associated degree of distension, rather than by the LV intracavitary pressure. Mechanoreceptor activity was attenuated by pericardial constraint in that removal of the pericardium was associated with increased DFdiastole; for a given value of intracavitary LVEDP, removal of the pericardium increased transmural LVEDP and segment length. When LVEDP was increased from ≈5 to 25 mm Hg by volume expansion, DFdiastole increased more in the absence of the pericardium than when the pericardium was closed, because the heart enlarged more after the pericardium had been removed. During systole, mechanoreceptor activity (DFsystole) was also greater after removal of the pericardium. This increase was related to increased systolic pressure, that increase probably mediated by a Frank-Starling mechanism.
The potentially substantial constraining effect of the pericardium on ventricular filling has been shown previously.8 9 11 13 When the pericardium is closed, transmural pressure, the true determinant of cardiac volume, is the difference between intracavitary pressure and pericardial pressure. When the pericardium is open and the lungs retracted, transmural pressure is equal to intracavitary pressure, because cardiac external pressure is zero. In the present study, at any value of LVEDP, removal of the pericardium significantly increased transmural LVEDP and LV end-diastolic segment length, as Hamilton et al12 recently showed for the right atrium and ventricle in dogs and in patients. Thus, it might have been anticipated that pericardial constraint would attenuate the volume-induced increase in DFdiastole by limiting the increases in transmural LVEDP and LV dimensions. Removal of the pericardium increased the slope of the relation between DFdiastole and LVEDP but had no effect on the slopes of the relations between DFdiastole and transmural LVEDP or LV segment length. Rather than LV intracavitary pressure, transmural LVEDP and volume are the direct determinants of diastolic LV mechanoreceptor activity.
There is evidence that interventions that reduce cardiac filling pressure (eg, lower-body negative pressure) may not necessarily decrease LV mechanoreceptor activity.6 7 14 15 16 A similar finding was also observed in the relation between right atrial pressure and the concentration of atrial natriuretic peptide. With the pericardium closed, right atrial pressure was increased from 2 to 8 mm Hg, but this produced no increase in atrial natriuretic peptide concentration. However, while right atrial pressure was maintained at 8 mm Hg, the pericardium was then opened, raising right atrial transmural pressure from 2 to 8 mm Hg and increasing atrial natriuretic peptide concentration.13 These phenomena may be particularly important in patients with congestive heart failure in whom pericardial pressure may already be elevated.9 11 16 17 Since lower-body negative pressure may lower pericardial pressure almost as much as it lowers LVEDP, transmural LVEDP may change only slightly, if at all. Previous studies of patients with heart failure have demonstrated decreased LV mechanoreceptor activity, despite significant increases in LVEDP.6 14 The decrease in cardiac vagal afferent activity has been implicated in the excessive neurohumoral stimulation seen in heart failure.6 Furthermore, paradoxical vasodilation responses during lower-body negative pressure were reported in patients with heart failure.7 14 15 In such patients, although lower-body negative pressure was associated with a significant reduction in cardiac filling pressure, calculated LV volume remained unchanged or actually increased16 and cardiac index increased.15 Thus, in patients with heart failure subjected to interventions that normally decrease LV volume, alterations in pericardial constraint may account for apparently paradoxical hemodynamics and LV mechanoreceptor activity. (As can occur in pulmonary embolism, volume may not change or may increase despite decreases in LVEDP.18 )
Thames et al4 studied the effects of changes in transmural pressure on LA and LV mechanoreceptor activity in closed-chest, spontaneously breathing cats. Although LA receptor activity increased at end inspiration relative to that during the remainder of respiratory cycle, LV mechanoreceptor activity was not altered during respiration, suggesting that LV mechanoreceptors are independent of transmural pressure. However, the atrium is more distensible than the ventricle.12 Thus, for a given rise in transmural pressure (assuming identical magnitudes of change in LA and LV transmural pressures during respiration), the LA might distend more than the LV. This might account, at least in part, for the observed absence of changes in LV mechanoreceptor activity during respiration.
We observed that removing the pericardium shifted the relations between DFdiastole and transmural LVEDP and end-diastolic segment length slightly rightward (P=NS). After the pericardium had been opened, a period of 20 to 25 minutes was required to decrease LVEDP from 25 to 5 mm Hg by graded hemorrhage. Thus, LV mechanoreceptor adaptation may be the mechanism for these apparent shifts. Although arterial baroreceptor resetting phenomena have been well documented,3 no prior study has assessed the characteristics of LV mechanoreceptor resetting during exposure to such elevated intracavitary pressures, transmural LVEDP ≈25 mm Hg being much higher than values encountered normally.12 Therefore, the exact mechanism for adaptation of LV mechanoreceptors remains to be determined.
In summary, the effects of pericardial constraint on LV mechanoreceptor activity were assessed. Compared at any given value of LVEDP, removal of the pericardium caused DFdiastole to increase significantly. The results suggest that LV transmural pressure or cardiac distension, which may be modulated by pericardial constraint, are the primary determinants of LV mechanoreceptor activity. Thus, the direction and magnitude of changes in transmural LVEDP or LV volume (rather than simply the change in the intracavitary pressure) should be related to changes in the LV mechanoreceptor activity.
Selected Abbreviations and Acronyms
|DFdiastole||=||diastolic discharge frequency|
|DFsystole||=||systolic discharge frequency|
|LV||=||left ventricle, left ventricular|
|LVEDP||=||LV end-diastolic pressure|
This study was supported by a grant-in-aid from the Alberta Heart and Stroke Foundation (Calgary). We thank Gerald Groves and Cheryl Meuk for skillful surgical assistance, Dr G.E. Lucier for technical advice and assistance in recording the nerve activity, and Dr I. Belenkie for helpful discussions. Dr Tyberg is a Medical Scientist of the Alberta Heritage Foundation for Medical Research (Edmonton).
Reprint requests to John V. Tyberg, MD, PhD, Departments of Medicine and Medical Physiology, The University of Calgary, 3330 Hospital Dr NW, Calgary, Alberta T2N 4N1, Canada.
- Received February 15, 1995.
- Revision received June 21, 1995.
- Accepted July 24, 1995.
- Copyright © 1995 by American Heart Association
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