Septal Function During Left Ventricular Unloading
Background Left ventricular (LV) unloading with mechanical support devices alters biventricular geometry and impairs right ventricular (RV) contractility, but its effect on septal systolic function remains unknown.
Methods and Results To evaluate the effects of LV volume and pressure unloading on septal geometry and function, LV preload was abruptly reduced by clamping left atrial pressure between 0 and −2 mm Hg in seven open-chest, anesthetized dogs by use of a pressure-control servomechanism to withdraw blood from the left atrium. With left atrial pressure clamping, maximal LV pressure decreased 30±12% (mean±SD) (P<.0001) and LV end-diastolic cross-sectional area (determined by two-dimensional echocardiography) decreased by 53±16% (P<.0001). This caused the septum to shift toward the left (RV septal free-wall dimension increased; P<.004) and flatten (radius of curvature increased; P<.0002), while LV septal free-wall dimension fell (P<.0001). Septal end-diastolic thickness increased 23±15% (P<.0005), reflecting a decline in septal preload. Systolic septal thickening decreased (P<.002), while systolic septal output (Septal Output=Septal Thickening×Heart Rate) fell from 30±17 to 15±22 cm/min (P<.002). This was associated with movement along the septal Frank-Starling equivalent (septal output versus end-diastolic septal thickness [preload] relation) to a less productive portion of the curve.
Conclusions LV unloading not only altered interventricular septal geometry but also reduced septal systolic thickening and output, all of which may contribute to impaired RV contractility during mechanical LV support.
Normal septal function is essential to the maintenance of adequate RV output during stress or ischemia of the RV free wall, but the mechanisms through which the septum influences RV systolic performance have only recently been appreciated. Since Banka and coworkers1 first demonstrated that the septum contributes importantly to both RV and LV systolic function, interest in the physiological circumstances that alter septal geometry and contractile state has increased. Septal function during pressure and volume unloading of the left ventricle is clinically important during the use of an LVAD for temporary support of patients with cardiogenic shock or when an LVAD is used as a bridge to transplantation or as a permanent replacement device. This device can dramatically alter the normal physiological milieu of the septum and has been associated with the development of RV failure in humans.2 3 4 5 6
LV volume and pressure unloading (preload reduction) has been shown to alter RV systolic mechanics in both closed-chest animals and open-chest humans.5 6 7 8 Mechanical LV support impairs global RV contractility, but in normal hearts or those with isolated RV free-wall ischemia, overall RV pump performance and mechanical efficiency do not fall because of a simultaneous and offsetting decrease in RV afterload.6 9 Previous studies from our laboratory and others4 5 6 10 also showed that the interventricular septum flattens and shifts toward the left with LV unloading, and the transseptal pressure gradient falls; however, the inability to measure septal thickness and geometry simultaneously in these previous studies has hindered evaluation of septal mechanics during LV support. Damiano and associates11 showed that RV function is highly dependent on contraction of the left ventricle and septum, with LV systolic forces responsible for >60% of RV contractile force. As the septum shifts away from the right ventricle, one would predict a decline in RV contractile force solely on the basis of systolic ventricular interdependence, a direct interaction due to anatomic coupling of the ventricles. Increasing levels of mechanical LV support cause the interventricular septum to move farther to the left, which further impairs RV contractility,6 but the effects of LV unloading on intrinsic septal function remain unclear. Does LV unloading depress systolic thickening of the interventricular septum, or is septal systolic function normal and its contribution to RV contractile force diminished merely by anatomic shifting consequent to changes in transseptal pressure? In the present study, the left ventricle was rapidly volume unloaded using a large-bore cannula inserted into the left atrium to reduce LAP to 0 or −2 mm Hg; this pressure was maintained at the desired target level with continued servo-controlled blood withdrawal. Using 2D epicardial echocardiography, we were able to quantify RV and LV size and shape and evaluate changes in septal thickening, septal geometry, and septal systolic function in response to rapid LV unloading.
Seven healthy dogs (weight, 25 to 30 kg) were premedicated with acepromazine maleate (0.05 mg/kg SC), anesthetized with thiopental sodium (25 mg/kg), and intubated and ventilated (Ohio Anesthesia Ventilator). Anesthesia was maintained with supplemental inhalational isoflurane (1% to 2%) only during the surgical preparation; intravenous fentanyl citrate (8 mg·kg−1·h−1) and diazepam (10 mg/h) were used during periods of data collection to minimize myocardial depression. A left thoracotomy was performed through the fifth intercostal space, and the heart was suspended in a pericardial cradle such that the LV center of mass was slightly higher than that of the left atrium. This position was selected to minimize the hydrostatic pressure difference between LVP and LAP measurements. Ultrasonic flow probes (14- to 16-mm perivascular probes with a T201D flowmeter; Transonic Systems, Inc) were placed around the aortic root and main PA to measure LV and RV output, respectively. Micromanometer-tipped pressure catheters (Millar Instruments Inc) were soaked in 39°C lactated Ringer's solution for 2 to 3 days before use to minimize drift to within +0.5 mm Hg and then calibrated carefully before and after each experiment in a temperature-controlled water bath with a fluid manometer as previously described.12 Catheters were then advanced through the right carotid artery into the mid-LV chamber near the mitral valve (Millar SPR-559), through a right femoral vein introducer into the RV chamber (Millar MPC-500), and through the RV free wall into the pulmonary arterial tree (Millar MPC-500). Another pressure catheter (Millar MPC-500) was secured to the external surface of a 42F venous cannula (TF046L; Research Medical, Inc), and after systemic heparin administration (300 U/kg), the cannula was inserted into the left atrium such that the pressure sensor and cannula holes came to rest at the level of the middle of the mitral valve commissures. Catheter and cannula positions were verified with epicardial echocardiography.
The LA cannula was connected to a computer-driven, pressure-control servomechanism as previously described.12 The computer software used to drive the pump was designed to allow continuous feedback–controlled suction through the LA cannula to maintain LAP at a predetermined level. After two baseline beats were recorded, the servo-pump mechanism was initiated during the third beat, and LAP was clamped at the desired level. The servo pump continuously withdrew blood from or infused blood into the left atrium as necessary to maintain LAP at the desired level for a minimum of three cardiac cycles.
Before initiation of data collection, UL-FS49, a highly selective and specific dromotropic agent that affects the sinoatrial node but does not significantly change QT interval, inotropic state, or systolic or diastolic blood pressure was administered as necessary to reduce the heart rate to 80 to 100 min−1 (0.25 to 0.5 mg/kg IV; Boehringer-Ingelheim). To minimize the effects of intrathoracic pressure variation, the respirator was temporarily interrupted at end expiration during data collection for ≈10 seconds. Simultaneous 2D epicardial echocardiographic images and hemodynamic data were obtained at LAP clamping levels of 0 and −2 mm Hg for all animals; data-acquisition runs containing premature ventricular contractions were excluded and repeated. Although data were acquired for all animals at both levels of LAP clamping, the observations reported herein include five of seven animals at LAP clamping of 0 mm Hg and six of seven animals at LAP clamping of −2 mm Hg. Arrhythmias were quite common with the rapid withdrawal of blood through the LA cannula; despite attempts to repeat runs with irregular beats, ectopy-free LAP control was not possible in all cases. Therefore, to exclude erroneous data, runs with atrial or ventricular premature beats or inadequate echocardiographic images were excluded from this analysis.
At the conclusion of the experiment, the dogs were killed by use of B-euthanasia (0.1 mL/lb IV; Schering-Plough Animal Health Corp), and proper positioning of the catheters and cannula was confirmed. All animals received humane care in compliance with the “Principles of Laboratory Animal Care” formulated by the National Society for Medical Research and the Guide for the Care and Use of Laboratory Animals prepared by the National Academy of Sciences and published by the National Institutes of Health (DHEW [NIH] publication 85-23, revised 1985). The study was approved by the Stanford Medical Center Laboratory Research Animal Review Committee and conducted according to Stanford University policy.
2D direct epicardial echocardiography was performed with the use of a 5.0-MHz transducer (77020 AC; Hewlett-Packard) to evaluate geometric changes of the left ventricle, right ventricle, and interventricular septum. Cross-sectional images were obtained of both the right and left ventricles at the LV mid–papillary muscle level (parasternal short-axis equivalent). A surface ECG signal and LAP tracing were simultaneously recorded on the echocardiographic images to allow proper temporal registration with the hemodynamic data at 30 Hz (every 33.3 ms) on .5-in videotape for later stop-frame analysis. All echocardiographic data were reviewed in real time, and segments of interest were transferred to a microcomputer (VAX 11/750; Digital Equipment Corp) through a time base corrector (AD 51, Hotronic, Inc) to synchronize video images with the image-processing system (IP8500, Gould Inc). Echocardiographic frames of interest were analyzed with software developed for our laboratory, and the system was calibrated with the use of the internally generated markers displayed by the echocardiogram.
During each data-acquisition run, seven channels of analog data were recorded (LVP, LAP, PA pressure, RVP, aortic flow, PA flow, and surface lead ECG) and digitized simultaneously at 240 Hz with the use of two 486-based microcomputers (486-33 and 486-50; JDR Microdevices Inc) with high-speed data-acquisition cards (DT 3831-G; Data Translation Inc) controlled by commercially available software (Labtech Control 3.2.0; Laboratory Technology Corp). This software system also controlled the servo-pump mechanism throughout the experiment.
Echocardiographic images were analyzed at both ED and ES. To coordinate the 240-Hz hemodynamic data and 30-Hz echocardiographic data, ED was defined as the time of peak ECG R wave, and ES was defined as the frame or time (number of frames beyond peak ECG R wave multiplied by 33.3 ms) of minimum LV echocardiographic area. All echocardiographic RV and LV endocardial tracings eliminated trabecular irregularities and cut through the base of the papillary muscles. Cross-sectional LV or RV area was then calculated as the area within the endocardial tracings for each ventricle. SFW dimensions were measured from the midpoint of the LV and RV endocardial free-wall perimeters to their respective endocardial septal surfaces, perpendicular to the septum; septal thickness was also measured along this line. Echocardiographic measurements included: RV and LV AreaED and AreaES, RV and LV SFWED and SFWES, and SeptED and SeptES. RV and LV APEDs were also measured, and RV and LV short-axis end-diastolic eccentricities (eED) were calculated to quantify ventricular shape: eED=(APED2−SFWED2)1/2/APED. Stroke area was computed for each ventricle as Stroke Area=AreaED−AreaES, and Sept-ST was calculated as Sept-ST=SeptES−SeptED (positive value represents thickening during systole).
Septal ROC at ED was quantified with the use of techniques described by Silverman et al13 and Hutchins et al.14 The LV endocardial surface was traced with the image-processing system, and the middle portion of the septal perimeter (excluding the anterior and posterior regions of insertion into the RV or LV free walls) was best fit by matching curves of known ROC etched on a transparent sheet. Septal curvature was measured independently in duplicate by two individuals to maximize accuracy. To decrease the influence of LV intracavitary volume on measurement of changes in ROC from loaded to unloaded beats, ROC was normalized using the ROCi as previously described.10 15 Assuming the LV cavity cross section to be perfectly circular, ROCi=(LV AreaED/π)1/2 and n-ROC=ROC/ROCi.
LVP, RVP, and TSP (LVP−RVP) were determined at ED (LVPED, RVPED, and TSPED), and mean developed (ejection) LVP, RVP, and TSP were calculated where the beginning of ejection was defined as the time of rapid upstroke of the aortic or PA flow signal and the end of ejection as the time of minimum LV echocardiographic area to allow matching of the hemodynamic and echocardiographic data. Maximal LVP and RVP were also determined (LVPmax, RVPmax). RV afterload was quantified with the use of pulmonary vascular impedance (input impedance plus characteristic impedance), calculated by use of Fourier analysis as previously reported.6 9 16 Input impedance describes the ratio of oscillatory pressure to oscillatory flow and depends on the cross-sectional area of the pulmonary bed and LAP. Characteristic impedance represents the pulsatile component of pulmonary flow and is influenced by vascular wall compliance and blood inertia. Effective Ea of the pulmonary vascular bed (RV Ea), which is a function of maximal RVP and SV, was also calculated to estimate RV afterload as RV Ea=RVPmax/SV.8 17 RV Ea represents a steady-state approximation of maximal pulmonary vascular impedance.
Global LV and RV SVs were determined by integrating aortic and PA flow, respectively, throughout systole; global SW was calculated for each ventricle as SW=SV×Mean Developed Pressure (Mean Ejection Pressure−ED Pressure). To quantify Sept-Output (septal displacement per minute), Sept-ST was multiplied by heart rate: Sept-Output=Sept-ST×(RR Interval×60/1000). Sept-Output was then plotted against end-diastolic thickness (septal preload) to examine the septal Frank-Starling equivalent.
All data are reported as mean±SD. The two normal “unloaded” baseline beats before LAP clamping were averaged (beats 1 and 2 in Figs 1⇓ and 2) and then compared with the initial “unloaded” beat after LAP clamping (beat 4 in Figs 1 and 2⇓⇓) with the use of Student's t test for paired comparisons and Hotelling's T2 test for multivariate analysis of related variables (Sept-ST and Sept-Output). Differences were considered significant at a level of P<.05.
Fig 1⇑ illustrates a typical control sequence taken from one animal with LAP clamping of −2 mm Hg, and Fig 2⇑ (A and B) demonstrates on a greatly expanded scale the differential effects of LAP clamping on measured LAP and LVP at both LAP set points (Fig 2A⇑, LAP clamping=0 mm Hg; Fig 2B⇑, LAP clamping=−2 mm Hg). After two baseline beats, LAP clamping was initiated to maintain LAP at the desired target pressure for the next two beats. Using this LAP-clamp servomechanism, we were able to decrease LAP significantly (Table 1⇓). When LAP clamping was set at 0 mm Hg (Fig 2A⇑), the servomechanism was able to lower mean LAP from 7.2±3.3 mm Hg at baseline to 0.8±1.1 mm Hg (P<.005); when LAP clamping was set at −2 mm Hg (Figs 1 and 2B⇑⇑), it was able to maintain mean LAP at −0.3±1.7 mm Hg (P<.0001). The physiological consequences were similar at the two LAP set-point levels; the 93% and 112% declines in mean LAP with set points of 0 and −2 mm Hg, respectively, were not significantly different (P>.36). LAP clamping also produced 68% (LAP=0 mm Hg) and 83% (LAP=−2 mm Hg) declines in LVPED (P>.24), 22% and 36% falls in LVPmax (P<.04), 66% and 77% drops in mean aortic flow (P>.51), 20% and 11% reductions in RVPED (P>.67), and no change in RVPmax or mean PA flow with either level of clamping (Table 1⇓). These findings are consistent with substantial pressure and volume unloading of the left ventricle during LAP clamping. Because the response was consistent with either level of clamping, the data from LAP clamping of 0 and −2 mm Hg are combined henceforth for brevity and clarity. Statistical analyses were performed separately for LAP clamp runs of 0 and −2 mm Hg, but the results were consistent and the conclusions were identical with those reported using the combined data. Typically, a 5- to 10-mm Hg pressure gradient existed between the RV and PA pressures (Fig 1⇑) in all animals at all times, presumably due to a hydrostatic pressure difference (right lateral decubitus position) and placement of the PA micromanometer into a branch PA; however, this pressure-differential artifact was stable on a beat-to-beat basis and unaffected by LAP clamping.
Typical echocardiographic images from the same animal illustrated in Figs 1 and 2⇑⇑ are shown in Fig 3A and 3B⇓⇓. In this animal with LAP clamping of −2 mm Hg, LV AreaED fell from 17.1 to 7.5 cm2, while RV AreaED increased from 11.5 to 13.4 cm2. For all animals with LAP clamping, LV preload (ie, LV AreaED) fell by 52% (P<.0001); LV stroke area and SV fell by 59% (P<.0004) and 73% (P<.0001), respectively; and global LV SW decreased 77% (P<.0006) (Table 2⇓). These findings all demonstrate substantial volume unloading of the left ventricle with LAP clamping. On the right side of the heart, RV preload (ie, RV AreaED) increased 21% (P>.03) during LAP clamping, but RV afterload decreased significantly. Although there was no change in PA characteristic impedance (281±68 versus 276±132 dyne s/cm5; P>.91), PA input impedance declined significantly from 809±330 to 606±274 dyne s/cm5 (P<.02). In addition, RV Ea, another reflection of RV afterload, dropped significantly from 1.8±0.6 to 1.6±0.5 mm Hg/mL (P<.02). RV stroke area increased fivefold with LAP clamping (P<.007). Although there was a trend for RV SV and SW to rise, these changes did not reach statistical significance (RV SV, P>.07; RV SW, P>.06) (Table 2⇓). The end-diastolic geometric configuration of both ventricles changed markedly (Fig 3A and 3B⇓⇓). Although RV SFWED increased (P<.004), RV APED did not change (P>.90), thereby resulting in the RV cross-sectional shape becoming less elliptical (ie, RV eED decreased; P<.003) (Table 2⇓). On the other hand, although both LV SFWED and APED decreased (P<.0001 for both), LV SFWED fell to a relatively greater extent, causing the LV shape to become more elliptical in the short-axis plane (eg, LV eED increased; P<.005).
With respect to septal geometry, a significant leftward shift occurred (increase in RV SFWED and decrease in LV SFWED) associated with the fall in TSPED from 2.6±1.5 to −3.8±1.9 mm Hg (P<.0001). Along with this leftward septal shift, the septum itself flattened; septal ROC more than doubled with LV unloading (P<.0002) (Table 3⇓), and n-ROC rose by greater than threefold (P<.0001). Fig 3⇑ (A and B) illustrates how the septum both flattened and shifted to the left; in this animal, RV SFWED increased from 2.2 to 2.9 cm, while LV SFWED decreased from 4.1 to 2.5 cm, resulting in the marked increase in septal ROC (septal flattening). Significant changes in septal mechanics also occurred in all animals (Table 3⇓). SeptED increased by 23% with LAP clamping (P<.0005). Thickening of the septum represents a decrease in fiber length or a reduction in septal preload. Furthermore, Sept-ST significantly declined (P<.002) and Sept-Output fell by 96% (P<.002). In addition, developed LVP dropped from 77±17 to 54±19 mm Hg (P<.0001) while developed RVP did not change (23±4 versus 23±4 mm Hg; P>.40), resulting in a significant decline in mean developed TSP (52±15 versus 33±15 mm Hg; P<.0001). Fig 4⇓ demonstrates the changes in the Sept-Output versus SeptED relation (Frank-Starling equivalent) during LAP clamping in all animals. While SeptED increased (a decrease in septal preload; see above), Sept-Output decreased; in most cases, the septum was working on a less-productive region of its Frank-Starling curve.
Henderson and Prince18 were the first to suggest in 1914 that the position of the interventricular septum could modulate interaction between the ventricles when they noted that the output of one ventricle decreased as the filling pressure of the contralateral ventricle increased. Since then, many investigators have demonstrated that ventricular interdependence is both a diastolic and systolic phenomenon.10 19 20 21 22 During diastole, as LVP and LV volume increase, the septum is “pushed” to the right; this causes RV diastolic pressure to rise and the RV end-diastolic pressure-volume relation to become steeper. Conversely, decreasing LV volume or LVP “pulls” the septum leftward, causing RV diastolic pressure to fall and the RV end-diastolic pressure-volume relation to flatten. These changes occur either with or without an intact pericardium.19 20 23 The left side of the heart has been shown to play a major role in assisting RV ejection. Damiano and coworkers11 demonstrated that the left ventricle and septum are responsible for >60% of the systolic contractile force of the right ventricle. Since Starr and colleagues24 first demonstrated in 1943 that isolated damage of the RV free wall does not produce clinical RV failure, others25 have shown that the RV free wall can be completely excised and replaced with an inert prosthetic patch with maintenance of adequate RV output as long as LV function is preserved and pulmonary vascular resistance is not elevated. Li and Santamore26 observed that RV function can be impaired in isovolumic rabbit hearts by reducing LV free-wall contractility: isolated LV free-wall ischemia reduced RV developed pressure by 49%, and surgical transection of the LV free wall from the apex to the base reduced RV developed pressure by 38%, which returned to normal after repair of the LV wall.26 It is important to remember, however, that the left-sided contribution to RV function comes from the septum as well as the LV free wall.10
Morphologically, the septum can be considered a part of the left ventricle, but it contributes importantly to the function of both ventricles in normal hearts. Banka and coworkers1 examined septal motion in humans using simultaneous RV and LV angiography and found that the septum thickened equally in both the RV and LV directions and also shortened along its apex-to-base longitudinal axis. Li and Santamore26 observed that injecting glutaraldehyde into the septum of isolated rabbit hearts depressed RV developed pressure by 37%, and Agarwal and colleagues27 demonstrated that isolated ischemia of the interventricular septum was associated with RV but not LV systolic dysfunction. Thirty minutes after ligation of the septal coronary artery in dogs, Agarwal et al27 observed a shift in the RV Frank-Starling relation (RV SW versus RVPED) downward and to the right (impaired RV systolic performance), while the LV relation did not change. This occurred in the presence of normal systolic shortening in the RV free wall but increased shortening (16%) in the LV free wall (an apparently compensatory response) as measured with the use of ultrasonic segment length crystals. They concluded that while septal ischemia did not provoke LV dysfunction, possibly due to “hyperfunction” of the nonischemic zones, the high dependency of RV function on normal septal contractility resulted in significant impairment of RV output during septal ischemia.27
More recently, Woodard et al,21 in an elegant study, isolated the systolic effects of LVP on RV mechanics by rapidly withdrawing blood from the left ventricle immediately after diastole via a large-bore LV apical cannula. With this preparation, they were able to quantify LV-to-RV systolic interaction independently of diastolic interference; the LV was not unloaded until systole had begun, and thus end-diastolic conditions were equal for both loaded and unloaded ejections. This becomes important when one notes that diastolic and systolic interactions tend to counteract each other during steady-state changes in LV or RV load. With rapid systolic unloading, mean developed LVP dropped by 63%, which caused a fall in mean developed RVP (14%), RV SV (18%), and RV SW (27%). This was associated with a relative leftward shift of the septum as LV SFW distance decreased and RV SFW distance increased at ES. Whether septal position was the cause or the effect of this systolic “cross talk” between the ventricles or whether septal function per se was impaired owing to the resultant change in TSP was not clear. Determination of the role of the septum in modulating the RV response to LV support would require not only an evaluation of septal contractility and load but a complete evaluation of the 3D geometric septal changes induced by LV unloading, which undoubtedly affects septal afterload.
Using myocardial markers to simultaneously assess 3D RV, LV, and septal geometry, we previously studied the effects of TSP on 3D septal position during LV unloading with an LVAD in closed-chest, conscious dogs.6 LV unloading was not rapid because the animals were allowed to achieve a steady hemodynamic state after the initiation of maximal LV support (100% LVAD flow). TSP fell from 4±4 to −5±4 mm Hg with LV unloading, causing movement of the interventricular septum to the left (14% decrease in LV SFW dimension, 11% increase in RV SFW dimension). The leftward septal shift was associated with a significant decline (−26%) in RV end-systolic elastance (slope of the end-systolic pressure-volume relation), a 15% fall in preload recruitable SW, and a 47% reduction in the slope of the dP/dtmax–end-diastolic volume relationship. Our inability to measure septal thickness in this preparation, however, did not allow us to determine if the decrease in global RV systolic mechanics was due to impairment of septal contractility (systolic thickening) or whether septal function was normal and its contribution to RV contraction was merely diminished by virtue of its leftward shift and flattening.
In the present study, peak LVP fell 30% with rapid LV unloading, which consequently decreased RV afterload (23% decline in PA input impedance, 8% fall in pulmonary Ea) and augmented RV preload (21% rise in RV end-diastolic cross-sectional area). Global RV output, which is a function of RV preload, afterload, and contractility, did not change significantly; although there was a tendency for RV SV and SW to increase, these changes were not consistent and did not reach statistical significance. Although we could not directly measure RV contractility in the present study, one can safely predict on the basis of earlier studies that because afterload fell, preload increased, and output did not significantly change, RV contractility did not improve and most likely declined in these normal canine hearts. This is consistent with previous findings of a 15% to 47% fall in RV contractility with mechanical LV support.4 6
This investigation focused on the geometric and intrinsic functional septal changes induced by LV unloading in an attempt to determine how this influenced RV systolic mechanics. Santamore and coworkers28 showed that RV contraction is the result of a decrease in the surface area of the RV free wall plus a reduction of RV SFW distance during systole. We found that as TSP fell, the interventricular septum moved toward the left and flattened, and the right ventricle developed a less elliptical cross-sectional shape as the RV SFWED increased with respect to the RV APED (RV short-axis eccentricity decreased; see Fig 3A and 3B⇑⇑). This configuration alone could be responsible for impaired RV contractility, because the septum is less able to contribute to RV ejection; moreover, we found that Sept-ST and Sept-Output were diminished. The septum normally thickens during systole, helping to expel blood from both ventricles, and the ability of the septum to thicken is determined in part by the contractile state of its muscle fibers. With LV unloading, Sept-ST decreased by 94% and Sept-Output fell by 96% in the setting of reduced septal preload. The combination of decreased septal output with an increase in septal end-diastolic thickness is predicted on the basis of the Frank-Starling relation (Fig 4⇑); the sarcomeres appeared to be working on a less productive portion of the Frank-Starling curve. Therefore, not only did LV unloading induce septal geometric changes that were disadvantageous to RV ejection, LV unloading also decreased septal systolic output. All of these changes may contribute to the reduction in RV pump function that is seen clinically during mechanical LV support.
Recently, using transesophageal 2D echocardiography, Kawai and associates29 analyzed regional RV function in 14 patients by artificially dividing the RV cross-sectional area into free-wall and septal portions on the basis of grids drawn from the RV center of gravity (at ED) to the junctions of the free wall and septum. Regional fractional area change was then determined before and after LVAD insertion. Fractional area change of the RV free-wall portion did not change, but fractional area change of the RV septal portion was 50% lower. Although this technique does not directly measure septal contractility, it implies a decrease in septal contractile force consistent with the findings of the current study.
Development of RV failure after the initiation of mechanical LV support is not a rare clinical phenomenon. Although RV systolic dysfunction has not been shown to occur in normal hearts or in hearts with isolated RV free-wall ischemia,6 8 9 it has been suggested that coexistent ischemia of the interventricular septum may precipitate RV systolic dysfunction in patients dependent on mechanical LV assistance. Daly and colleagues30 found that isolated septal ischemia during bypass of the left side of the heart in open-chest calves decreased RV developed pressure by 29% and RV fractional area change (measured by use of 2D epicardial echocardiography) by 66%. With reperfusion of the septal arteries, these load-dependent measures of RV pump performance returned toward normal. In addition, Sept-ST fell with LV assistance and decreased further after septal ischemia but returned to its preischemic level with septal reperfusion. Daly et al30 concluded that because the septum plays a major role in RV ejection, further reduction of septal contraction due to ischemia could potentially provoke clinical RV failure during LVAD support.
In our experimental preparation, all animals were able to generate negative LVPs (or LV suction) with an intact, normal mitral-valve apparatus and LAP clamping ≤0. During early diastole when LAP clamping was 0 mm Hg, minimum LVP decreased from a baseline value of 3.3±1.7 to 1.2±1.2 mm Hg in the initial clamped beat and fell to −1.3±1.8 mm Hg during the subsequent beat. With LAP clamping at −2 mm Hg, minimum LVP fell from a baseline value of 3.9±1.3 to 0.4±1.1 mm Hg in the initial clamped beat and to −1.8±1.9 mm Hg during the subsequent beat. LV filling occurs for the most part due to the AV pressure gradient, and if LAP is 0, LVP must be negative to produce filling. It is becoming increasingly clear that LV suction plays a significant role in diastolic filling in times of stress and possibly in cardiac disease states.12 31 32 33 34 35 In our preparation, when LAP was decreased to ≤0, the normal LA-LV pressure gradient was abolished; however, the left ventricle generated negative pressures that maintained LV filling. Negative transmural LVPs as low as −30 mm Hg have been reported with various techniques used to occlude the mitral annulus rapidly at precise times (eg, ES) to prevent LV filling (or LV volume clamping).31 32 33 Although these studies unequivocally demonstrate the presence of LV suction, the myocardial mechanisms underlying this process remain incompletely characterized.
As LVP fell below zero with LAP pressure-clamping, the interventricular septum both flattened and thickened throughout diastole, creating a half-moon shape with respect to the left ventricle at ED in lieu of its more normal circular configuration. Similar motion of the septum during early diastole has been observed clinically by Weyman and associates36 in patients with severe mitral stenosis. Using transthoracic echocardiography, they noted that the septum flattened and moved to the left during early diastole, but then, presumably after the initial rapid-filling phase, the septum moved rightward to regain its normal circular configuration before ejection. Weyman et al36 speculated that this early leftward shift was due to unequal filling of the ventricles, with the right side filling much faster than the left owing to the substantial obstruction to flow across the stenotic mitral valve. Patients with mitral stenosis were subsequently found to develop negative LVPs (suction) at rest,34 but the role of the septum in the generation of LV suction remains unclear. During diastolic filling, the ventricular wall usually becomes thinner; however, in the current study, we found that the septum flattened and thickened with LAP clamping. Negative LVPs were produced in this preparation while septal thickening appeared to impede LV filling. Could this apparent dysfunctional septal movement actually be contributing to LV filling, or do negative LVPs develop despite abnormal septal motion? It is likely that the thick, flat, nonfunctioning septum associated with LV unloading observed in this preparation did not contribute substantially to the development of negative LVPs, which would suggest that LV suction is not dependent on the interventricular septum. Additional investigation with the use of more sophisticated techniques of evaluating 3D LV wall geometry will be necessary to define the mechanical basis of LV suction.
This experiment evaluated anesthetized open-chest dogs with presumably normal cardiac function, and although attempts were made to minimize the negative inotropic and arrhythmogenic effects of general anesthesia through the use of fentanyl and benzodiazepines instead of inhalational agents, this preparation is not completely analogous to the intact, closed-chest, conscious state. However, all conditions (open chest, open pericardium, level of anesthesia, etc) were identical during the baseline and the LAP clamped beats, except for the intended perturbation.
Throughout this study, RV endocardial echocardiographic cross-sectional area was used as an estimate of RV volume. Although this is not as accurate as measuring 3D RV volume with myocardial markers,6 Morita et al8 demonstrated that RV area correlated well (r=.96±0.03) with known intracavitary latex balloon volumes in excised canine hearts and was independent of changes in LV balloon volume.
After implantation of the LA cannula and multiple intracardiac monitoring devices, it was not possible to close the pericardium in a physiological manner. Although the absolute magnitude of the pericardial influence on intracardiac pressures and ventricular function remains incompletely defined, it is widely accepted that the pericardium significantly influences diastolic ventricular interaction and also modulates systolic interaction.19 20 23 The clinical application in which we were ultimately interested, however, was that of LVAD use in humans, in whom it is neither possible nor desirable to close the pericardium with all the cannulas in place. Therefore, the open-pericardium preparation used in the current experiment is representative of the clinical scenario. In this preparation, we found that rapid LV volume unloading not only caused the interventricular septum to shift to the left and flatten but also decreased Sept-ST and Sept-Output, all of which may contribute to impaired RV function during mechanical LV support.
Selected Abbreviations and Acronyms
|APED||=||end-diastolic anterior-posterior dimension|
|AreaED||=||end-diastolic endocardial cross-sectional area|
|AreaES||=||end-systolic endocardial cross-sectional area|
|LAP||=||left atrial pressure|
|LVAD||=||left ventricular assist device|
|LVP||=||left ventricular pressure|
|LVPED||=||end-diastolic left ventricular pressure|
|LVPmax||=||maximal left ventricular pressure|
|n-ROC||=||normalized radius of curvature|
|ROC||=||radius of curvature|
|ROCi||=||idealized radius of curvature|
|RVP||=||right ventricular pressure|
|RVPED||=||end-diastolic right ventricular pressure|
|RVPmax||=||maximal right ventricular pressure|
|SeptED||=||end-diastolic septal thickness|
|SeptES||=||end-systolic septal thickness|
|Sept-Output||=||septal systolic output (septal displacement per minute)|
|Sept-ST||=||septal “stroke dimension” or systolic thickening|
|SFW||=||septal free wall|
|SFWED||=||end-diastolic septal free-wall dimension|
|SFWES||=||end-systolic septal free-wall dimension|
|TSPED||=||end-diastolic transseptal pressure|
This study was supported by grants HL-48837 and HL-29589 from the National Heart, Lung, and Blood Institute and the Veterans Administration Medical Research Service. Drs Moon and DeAnda were also supported by NHLBI Individual National Research Service Awards HL-08532 and HL-08928, and Drs Moon, DeAnda, and Komeda are Carl and Leah McConnell Cardiovascular Surgical Research Fellows. The authors gratefully acknowledge the assistance of Phoebe E. Taboada in the preparation of this manuscript, and Yasuko Tomizawa, MD, PhD, and Conrad M. Vial, MD, for their assistance in the surgical preparations, as well as the technical assistance of Geraldine C. Derby, RN, BS, Cynthia E. Handen, BA, and Mary K. Zasio, BA.
- Received July 29, 1996.
- Revision received October 16, 1996.
- Accepted October 27, 1996.
- Copyright © 1997 by American Heart Association
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