EXPERIMENTAL STUDIES
Determinants of forward pulmonary vein flow
An open pericardium pig model
Paolo Barbier, MDa,1,
Steve Solomon, PhDa,2,
Nelson B. Schiller, MD, FACCa and
Stanton A. Glantz, PhD, FACCa
a Cardiovascular Research Institute and Department of Medicine, University of California, San Francisco, San Francisco, California, USA
Manuscript received June 3, 1999;
revised manuscript received December 30, 1999,
accepted February 21, 2000.
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Abstract
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OBJECTIVE
To elucidate determinants of pulmonary venous (PV) flow.
BACKGROUND
Right ventricular (RV) systolic pressure (vis a tergo), left atrial (LA) relaxation and left ventricular (LV) systole and relaxation (vis a fronte) have been suggested as determinants of the pulmonary venous (PV) anterograde Doppler flow velocities, but their relative contributions to those flow velocities have not been quantified.
METHODS
We analyzed, by multiple regression analysis, the determinants of PV anterograde velocities in an open-pericardium, paced (70 and 90 beats/min) pig model in which LA afterload was modified by creating LV regional ischemia (left anterior descending coronary artery constriction). We measured high fidelity LA, LV and RV pressures and Doppler flow velocities (epicardial echocardiography). We calculated LV tau, LA relaxation (a through x pressure difference divided by time, normalized by a pressure), LA peak v through x and RV systolic through LA peak v (RVSP-v) pressure differences, LV ejection fraction, long-axis shortening, stroke volume (LV outflow integral x outflow area) and LA four-chamber dimensions, Doppler transmitral and PV flow velocities and velocity-time integrals.
RESULTS
Left ventricular regional ischemia increased mildly LA y trough pressure (8 ± 1 vs. 6 ± 1 mm Hg, p = 0.001). Left ventricular stroke volume (coefficient: 0.5 cm/ml, SE: 0.2, p = 0.005) and LA peak v pressure (coefficient: –0.8 cm/mm Hg, SE: 0.3, p = 0.008) determined the PV total systolic integral. Left atrial relaxation determined both PV early systolic peak velocity and integral (coefficient: –0.8 cm/mm Hg, SE: 0.3, p = 0.04). Left atrial maximum area (coefficient: 2 cm–1, SE: 0.7, p = 0.01) and RVSP-v (coefficient: 0.1 cm/mm Hg, SE: 0.05, p = 0.03) determined the late systolic integral. The PV total systolic integral determined both PV early diastolic peak velocity and integral (coefficient: 1.2, SE: 0.2, p = 0.001).
CONCLUSIONS
In an experimental model of LV acute ischemia of limited duration, the main independent predictors of PV systolic anterograde flow velocities are LA relaxation and compliance (LA peak v pressure) and LV systole—all vis a fronte factors. In the setting of mildly increased LA pressures, PV systolic flow (LA reservoir filling) is an independent predictor of PV early diastolic flow (LA early conduit).
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Abbreviations and Acronyms
| | ABD | = automated border detection algorithm | | ANOVA | = analysis of variance | | ECG | = electrocardiogram | | LA | = left atrium or atrial | | LV | = left ventricle or ventricular | | PV | = pulmonary vein | | RV | = right ventricle or ventricular |
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Pulsed Doppler analysis of pulmonary vein (PV) flow reveals a four-wave pattern. The first two anterograde systolic waves occur during the left atrial (LA) reservoir phase and left ventricular (LV) systole. The third anterograde early diastolic wave occurs during LV relaxation and early rapid filling (the LA conduit phase). The fourth retrograde (into the PVs) late diastolic wave occurs during LA contraction. The determinants of the fourth wave are atrial contraction and LV end-diastolic pressure (1,2). In contrast, the determinants of the PV systolic and early diastolic waves have not been quantitated.
The determinants of the two systolic waves (i.e., the systolic PV flow pattern) are still debated and have been ascribed to vis a fronte factors—LA relaxation (3–5) and LV systole through the descent of the cardiac base (3,5,6)—or vis a tergo factors—right ventricular (RV) systolic pressure transmitted through the pulmonary circulation (7,8). The main determinants of PV early diastolic flow have been suggested to be LV relaxation and early transmitral filling because of the temporal correspondence of the transmitral and PV early diastolic waves (1,6,9–11). However, we recently suggested, using an LA pressure-dimension analysis, that elastic energy stored by the atrium during reservoir may be returned during the following early conduit phase (12). Thus, LA reservoir function may influence the ensuing early conduit phase.
This study quantifies the determinants of the PV anterograde systolic and diastolic flow waves in an open-pericardium pig model of LV regional supply ischemia of limited duration. Regional LV ischemia increases LV diastolic pressure and, hence, LA afterload and increases LA pressures mildly shifting the LA pressure curve up and modifying LA function and PV inflow. This model of LA pressure increase, in contrast with the model that uses volume infusion to increase LA preload and pressure (9,13,14), reproduces changes in LA pressure and function that may occur during acute coronary artery disease or mild congestive heart failure in humans.
We recently studied the determinants of LA area changes during reservoir (reservoir function) in this same open-pericardium pig model (12). Left atrial relaxation and systolic descent of the cardiac base were, respectively, the main determinants of two, early and late, LA reservoir phases (similar, but not identical to, the PV early and late systolic flow waves). This study uses data collected in the same experiments to address two questions: Is vis a fronte (LA relaxation and the systolic descent of the cardiac base) or vis a tergo (transmitted RV systolic pressure wave) the main determinant of PV systolic flow? Are LV relaxation and early filling the main determinants of the PV early diastolic flow? We found that vis a fronte related factors are the main determinants of the two PV systolic waves and that the total systolic integral determines the ensuing PV early diastolic wave.
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Methods
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This article reports results collected in the same experiments previously reported (12,15) to minimize the number of animals used. Twelve juvenile Yorkshire pigs (weight = 42.3 ± 0.4 [SEM] kg) were studied using an open-chest, open-pericardium model of LV regional supply ischemia at two different heart rates. Our protocol was approved by the University of California San Francisco Committee on Animal Research. Methods have been described in detail previously (12).
Surgical preparation, instrumentation and echocardiographic recordings.
The animals were placed in the supine position, anesthetized and ventilated mechanically (room air supplemented with oxygen). We created a pericardial cradle after midline sternotomy and partial rib excisions to ensure adequate epicardial positioning of the ultrasound system (Hewlett Packard Sonos 2500, Andover, Massachussets) transducers (2.5/3.5 and 5.0 MHz). We placed 5F Millar micromanometer-tipped catheters in the mid LV, RV and LA cavities and into a left lower PV, guided by echocardiography (Fig. 1). The catheter was inserted at a depth of 2 to 3 cm into the vein to record PV pressure (Fig. 2A). In a subset of pigs, the catheter was wedged retrograde into the vein and pressures recorded during pullback into the PV sinus (Fig. 2B). Pacing electrodes were secured to the right atrial appendage. A C-clamp constrictor was placed around the left anterior descending coronary artery to reduce flow and regional myocardial shortening, which was measured with two pairs of segment-length ultrasonic crystals (Sonometrics, London, Ontario, Canada) inserted in the endocardium into the mid-anterior wall (ischemia region) and into the basal lateral wall (reference region). A single-lead electrocardiogram (ECG) was recorded and used as the reference point (peak of the R wave) to synchronize echocardiographic measurements. All recordings were digitized at 200 Hz with the respirator turned off at end expiration and stored in a personal computer for off-line analysis.
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Figure 1 Epicardial cross-sectional longitudinal examination of the left atrial (LA) cavity, a pulmonary vein sinus (s) and a left lower pulmonary vein (v) (from pig # 566). (A) The LA high-fidelity catheter (white arrow) is advanced in and indicates a lower left pulmonary vein. (B) Color Doppler inflow into the LA chamber from the pulmonary vein. The white asterisk indicates the pulmonary vein.
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Figure 2 Example of synchronous left atrial (LA) and pulmonary vein (PV) tracings with the respective a and v peak pressures and x and y nadir pressure points. (B) PV pressure pullback tracing. Top panel, from left to right: the Millar pressure catheter is slowly withdrawn from a retrograde wedge position deep within a left lower PV to the PV sinus in the LA cavity. Lower left and right panels: magnification of LV and PV pressure tracings, respectively, near the Millar catheter wedge position and proximal to the PV sinus. The thin line represents the LV pressure, and the thick line the PV pressure tracing. a = left atrial peak a wave pressure; ECG = electrocardiogram; LAP = left atrial pressure; LVP = LV pressure; PVP = PV pressure; v = left atrial peak v wave pressure; x = left atrial x pressure nadir; y = left atrial y pressure nadir.
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From the apex we obtained four- and two-chamber LV cavity biplane, four-chamber LA cavity monoplane, LV outflow tract echocardiographic and mitral tip pulsed Doppler flow velocity recordings. The LA area was obtained in real-time using the automated border detection algorithm (ABD) (Hewlett Packard, Andover, Massachusetts) of the ultrasound machine. Diastolic LV filling was measured with pulsed Doppler transmitral annular flow. Cardiac output was calculated by measuring LV outflow tract area and velocity in the apical five-chamber view. From the posterosuperior LA wall, we located one of the left PV sinuses with cross-sectional and color Doppler echocardiography and recorded pulsed Doppler PV flow velocities by positioning the sample volume 5 mm proximal to the orifice of a lower vein into a PV sinus as previously defined (12) (Fig. 1). The anatomy of the PV sinus was constant, enabling a uniform sample site throughout the protocol. The PVs are multiple and arranged asymmetrically in the pig, so PV cross-sectional area cannot be calculated. No attempt was made to quantitate PV flow, but we analyzed changes in the PV flow velocity pattern to infer changes of overall LA inflow. We used Doppler color flow visualization to screen for mitral and tricuspid regurgitation (Nyquist limit was set at 60 cm/s). Recordings were stored in S-VHS videotape and measured off-line with commercial software (Tomtech Imaging Systems, Boulder, Colorado).
Protocol.
Regional LV ischemia was obtained by tightening the constrictor for approximately 15 min to achieve a 20% decrease in absolute segment-length shortening of the anterior wall crystals. Right atrial pacing was performed with 1:1 atrioventricular conduction after inducing bradicardia with the calcium blocker zatebradine (ULFS 49, 2 mg/kg), a selective sinus node inhibitor. Tracings of LV four- and two-chamber views, LA ABD areas, LV outflow velocities and PV flow velocities were obtained within a 5 min interval together with hemodynamic data during baseline and ischemia, each during pacing at 70 and 90 beats/min.
Measurements.
Echocardiographic and Doppler measurements were performed by digitizing and averaging three to five consecutive cardiac cycles. Hemodynamic data were averaged over 15 cardiac cycles that included the echocardiographic cycles.
Hemodynamic measurements.
LV
We measured LV peak systolic and minimum pressures. We calculated LV end-diastolic pressure and the time constant of isovolumic relaxation, tau, as previously reported (15). The cross-over point of LA and LV pressures in early diastole at mitral valve opening was measured from the matched LA and LV pressure tracings. The LV cross-over to minimum pressure difference was calculated.
LA, PV and RV
We measured LA peak a (aLA), peak c, x trough (xLA), peak v (vLA), y descent (yLA) and their timings, mean LA pressure (mLA) and computed the aLA to xLA and vLA to xLA pressure differences. We computed a LA relaxation index (12) as: ([aLA – xLA]/aLA)/(tx – ta), where tx and ta are the timings of x trough and peak a pressure. The PV pressure tracing resembled the LA pressure tracing (Fig. 2A). Thus, we measured the PV peak a (aPV), x trough (xPV), peak v (vPV) and y descent (yPV). To quantify the influence of the PV to LA pressure gradient on PV flow velocities, we calculated the respective PV to LA pressure gradients: (aPV–aLA), (xPV–xLA), (vPV–vLA) and (yPV–yLA). We measured RV peak systolic pressure. To quantify the influence of the RV to LA transpulmonary pressure gradient during RV systole (7,8,16) on PV flow, we computed the RV systolic pressure to LA peak v pressure difference. The latter has been described as the result of the transmission of the RV systolic pressure wave through the pulmonary circulation, delayed in time (8,16).
Electrocardiographic measurements.
The R-R interval and the atrioventricular conduction time (time from end P wave to peak R wave) were measured.
Echocardiographic cross-sectional measurements.
Biplane LV (four- and two-chamber) end-diastolic (ml) (at ECG R wave) and end-systolic (at minimum LV dimension) volumes (area-length method), LV ejection fraction and systolic shortening of the LV long axis (a measure of the systolic descent of the mitral annulus, a vis a fronte factor) were calculated. The midsystolic LV outflow tract area was calculated from its diameter assuming a circular orifice.
Pulsed doppler measurements.
Three waves were consistently observed on the PV flow velocity tracings (Fig. 3A). The fourth, late diastolic flow reversal wave after atrial contraction, was observed in only 6 out of 12 pigs (50%) and was not analyzed in this article. We measured peak velocity (cm/s), velocity-time integral (cm), time to start, peak and end (ms) and duration of both early and late systolic flow waves (early wave duration = time to beginning of late wave minus time to beginning of early wave; late wave duration = time to end of late wave minus time to beginning of late wave) and of total systolic flow. We measured peak velocity, velocity-time integral and deceleration time of the early diastolic wave. We calculated the PV total systolic/diastolic velocity-time integral ratio. To separate each flow wave when flow velocity was not zero, we used the point of flow variation at the outer border of the velocity profile (Fig. 3A). From the transmitral flow velocity tracing, we measured the early diastolic peak velocity, velocity-time integral and deceleration time. We measured the LV outflow velocity-time integral (cm) and the time to start, peak and end of LV outflow (ms) (Fig. 3B). Left ventricular stroke volume was calculated as: velocity-time integral x outflow tract area and cardiac output as: LV stroke volume x heart rate. Left ventricular ejection time was calculated as: time to end minus time to start of LV outflow.
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Figure 3 (A) Example of pulsed Doppler PV flow velocity tracing from pig # 565 (baseline paced at 70 beats/min). White arrow indicates 20 cm/s pulsed Doppler velocity scale. Thick white arrow points at missing end-diastolic reverse wave. Black arrow indicates point of flow velocity nadir between the late systolic and early diastolic waves. (B) Example of pulsed Doppler left ventricular outflow tract (LVOT) velocity tracing from pig # 564 (baseline paced at 70 beats/min). a = start of LVOT velocity; b = peak LVOT velocity; c = end of LVOT velocity; D = early diastolic wave; ES = early systolic wave; LAP = left atrial pressure tracing; LS = late systolic wave; Ppace = right atrial pacing artifact; R = ECG R wave.
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Analysis of ABD tracings and pressure-ABD area curves.
We measured maximum and minimum LA ABD areas (cm2), the LA area before atrial contraction (at the end of the ECG P wave) and the area at slope change about halfway through LA filling, as previously defined (12). This area marked the transition from a faster to a slower LA filling phase, determined respectively by LA relaxation and the systolic descent of the mitral annulus (12). We calculated total reservoir area change (maximum minus minimum area, cm2) and its duration (time of maximum LA area minus timing of minimum LA area, ms), indexes of LA reservoir function; early reservoir area change (LA area at slope change minus LA minimum area), its duration (timing of LA area at slope change minus time of LA minimum area) and early mean filling rate (early area change/duration, cm2/s); late reservoir area change (LA maximum area minus LA area at slope change), its duration (timing of LA maximum area minus timing of LA area at slope change) and late mean filling rate (late area change/duration); LA stroke area (LA area before atrial contraction minus minimum area, cm2), fractional shortening (stroke area/area before atrial contraction, percentage) and mean ejection rate (stroke area/[timing of minimum area to timing of area before atrial contraction], cm2/s).
The ABD curve has a random time delay with respect to the pressure curve. To synchronize pressure and area data we superimposed (Fig. 4) the analog ABD and pressure curves and shifted the ABD tracing to align the LA area point before atrial contraction with the beginning of the LA pressure a wave and the end of the ECG P wave (12). We constructed LA pressure-area curves, which consist of two, a and v, loops and computed the areas of both (mm Hg x cm2) in each pig. We then plotted the pressure/area points corresponding to the LA pressure x trough and peak v and calculated an index of LA chamber stiffness as the slope connecting these two pressure/area points (12). This segment approximates the ascending limb of the LA pressure/area v loop, which is related to the stiffness characteristics of the LA chamber (17).
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Figure 4 From top to bottom, synchronized ECG, left atrial (LA) ABD (thin grey line), pressure (thick white line), pulsed Doppler pulmonary vein flow (PVF) and pulsed Doppler LV outflow tract (LVOT) velocity tracings (from pig # 566, baseline paced at 70 beats/min). The PVF late diastolic retrograde wave has been omitted for clarity. White vertical arrows indicate 20 cm/s pulsed Doppler velocity scale. White dotted lines indicate start and end of left ventricular ejection. a = LA peak a pressure; Amax = maximum LA area; Aac = LA area before atrial contraction; D = diastolic PVF wave; ES = early systolic PVF wave; LS = late systolic PVF wave; P = ECG P wave; R = ECG R wave; v = LA peak v pressure; x = LA x trough pressure.
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Reproducibility.
Echocardiographic measurements were performed by one of the investigators (P.B.). Intraobserver measurement variability was quantified by comparing measurements made three months apart with a Bland-Altman analysis for selected variables. No correlation was found between means and differences for the variables analyzed. The SDs of the differences were: 0.2 cm2 for LA maximum area, 0.2 cm2 for LA end-diastolic area, 3 ml for the four-chamber LV end-diastolic volume, 2.5 cm/s for the mitral peak early wave velocity, 1.8 cm/s for the pulmonary vein peak early systolic wave, 0.6 cm for the PV total systolic velocity-time integral.
Statistical analysis.
The effects of ischemia and heart rate (and their interaction) were analyzed using two-way repeated-measures general linear model analysis of variance (ANOVA). The tables report the least squares means and standard errors from the ANOVA. To test for a linear relationship between two variables across the experimental conditions, allowing for between-pig differences, we used a multiple regression in which effects-coded dummy variables were included to account for between-pig differences (18). For example, PV flow early systolic integral (cm) = b0 + brelax relax + Spi Pi, where relax = the LA relaxation index (cm x ms) and Pi = 1 if Pig I, –1 if Pig 12, 0 otherwise. The coefficient brelax represents the change in systolic integral per change in LA relaxation index, averaged across all pigs after allowing for between-pig differences in mean values. A significant p value associated with this coefficient indicates a significant linear relationship between these two variables. b0 represents the intercept of the average line. These coefficients and their standard errors are reported (we do not report the pi coefficients since they simply quantify between-pig differences). We used the same procedure to analyze the independent predictors of all the PV flow parameters. The independent variables used are shown in Table 1. Stepwise multiple regression analysis using all the variables described in the Methods section was used to screen for significant predictors of the above mentioned dependent variables.
Computations were done using SPSS for Windows version 7.5 with p < 0.05 considered significant. Results are presented as mean ± SEM.
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Results
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Analysis of baseline paced at 70 beats/min.
Left and right ventricular and LA baseline hemodynamics and LV biplane volumes and systolic function were typical for an anesthetized open-chest pig, as previously reported (12). Previously unreported values of LV crossover-minimum pressure difference and of LA y trough pressure are presented in Table 2. The LV crossover-minimum pressure difference at baseline correlated positively with the mitral valve peak early velocity and negatively with the PV diastolic wave deceleration time across pigs (Table 3).
We observed a pressure gradient between the PV and the LA cavity, which was constant throughout the cardiac cycle, such that the PV pressure curve resembled the LA pressure curve shifted upwards (Table 2, Fig. 2A). In the PV wedge position, we recorded a pressure curve that recalled a delayed pulmonary artery pressure curve. At pullback from the PV wedge position, the PV-LA pressure gradient decreased slightly and disappeared only after crossing the PV orifice with the catheter (Fig. 2B).
In the baseline paced at 70 beats/min, acceleration of the PV early systolic flow wave was concomitant with the peak a through x trough pressure fall, the previously defined (12) LA early reservoir area change and acceleration of LV outflow (Fig. 4). The timing of the PV peak early flow velocity occurred at the LA pressure x trough (Fig. 4) and both the timings of the beginning and the end of the PV early systolic flow wave correlated with the timing of the LA pressure x trough (Table 3). Acceleration of PV late systolic flow occurred during increasing LA x trough through v peak pressure gradient, LA late reservoir phase and LV outflow deceleration (Fig. 4). Pulmonary vein late systolic peak velocity occurred at LA maximum area (Fig. 4). The PV late systolic peak velocity and velocity-time integral and the total systolic velocity-time integral correlated positively with both LA maximum area and cardiac output (Table 3), whereas the late systolic integral correlated with both LA peak v pressure and RV systolic to LA peak v pressure difference. The PV total systolic integral was greater than the diastolic integral; the total systolic/early diastolic integral ratio exceeded 1.5 (main effect of three-way ANOVA: p = 0.003; interactions between main effect and heart rate or ischemia: p = ns). No correlations were found between PV early diastolic peak velocity, deceleration time or velocity-time integral and corresponding mitral valve indexes (Table 3).
Effects of ischemia and heart rate on pulmonary venous pressure and doppler anterograde velocities.
Though LV regional ischemia increased LA pressures (12), it did not significantly change PV pressures (Table 2). Consequently, we observed a trend towards a decrease of the PV-LA pressure gradient during the cardiac cycle (Table 3). The PV early diastolic velocity-time integral decreased (although peak velocity did not change) (Table 3). Consequently, the total systolic/diastolic integral ratio increased during LV ischemia because the total systolic integral did not change. We have previously reported the effects of LV ischemia on the systolic velocities (12).
Increasing heart rate to 90 beats/min decreased the LV crossover-minimum pressure difference and PV peak a and v pressures. The PV early diastolic peak velocity and velocity-time integral decreased (Table 2).
Independent predictors of the systolic pulmonary venous flow waves.
The determinants of both PV early systolic peak velocity and velocity-time integral were related to LA a through x pressure difference and LA relaxation index (both vis a fronte factors), respectively (Table 1, Fig. 5). Thus, the early systolic PV flow wave was determined only by the extent of LA pressure fall during LA relaxation. In contrast, we had previously shown that the LA area change during the early reservoir phase (simultaneous to the PV early systolic wave) was also related to the preceding LA contraction (12).
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Figure 5 (A) Examples of pulsed Doppler recordings of pulmonary vein flow (PVF) from pigs # 564, 566 and 569 at baseline paced at 70 beats/min (left panels) and ischemia paced at 70 beats/min (right panels). (B) Examples of left atrial (LA) pressure tracings (thick lines) from the same pigs, at baseline paced at 70 beats/min (left panels) and ischemia paced at 70 beats/min (right panels). White vertical arrows indicate 20 cm/s pulsed Doppler velocity scale. Note overall positive relation between LA peak a to x trough pressure difference and PVF early systolic peak velocity and inverse relation between height of LA pressure peak v wave or x trough and peak PVF late systolic wave velocity-time integral or peak velocity. The PVF late diastolic retrograde wave has been omitted. a = LA peak a pressure; c = LA peak c pressure; D = diastolic PVF wave; ECG = electrocardiographic tracing; ES = early systolic PVF wave; LS = late systolic PVF wave; Ppace = right atrial pacing artifact; R = EKG R wave; v = LA peak v pressure.
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The determinants of the PV late systolic peak velocity were related to LA pressure (x trough) and dimension (maximum area), both vis a fronte factors, whereas the determinants of the velocity-time integral were related to both vis a fronte (LA maximum area) and vis a tergo (the transpulmonary pressure difference between the RV peak systolic pressure and the LA peak v pressure) (Table 1, Fig. 5).
The determinants of the PV total systolic velocity-time integral were LV stroke volume and LA peak v pressure, both vis a fronte factors (Table 1, Fig. 5). The bivariate analysis using the baseline data revealed that the transpulmonary RV-LA pressure difference did correlate with the total systolic velocity-time integral (coefficient =0.125 cm/mm Hg, SE = 0.06, p = 0.04; Table 3), but this relation was not significant in the multivariate analysis (Table 1) that was based on more data and accounted for between-pig differences.
Independent predictors of the early diastolic pulmonary venous flow wave.
Surprisingly, the multivariate analysis found no significant relation between PV and mitral valve early diastolic flow wave indexes or between PV early diastolic wave and LV relaxation. Pulmonary vein early diastolic peak velocity and velocity-time integral were both independently predicted by the preceding PV systolic velocity-time integral (Table 1). Thus, PV systolic inflow into the LA during the reservoir phase was an independent predictor of the PV early diastolic flow wave during the LA early conduit phase.
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Discussion
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We demonstrate that vis a fronte related factors predominate over vis a tergo in determining both the early and late PV systolic flow waves and that the main determinant of the PV early diastolic flow wave (LA conduit inflow) in our model of mild LA pressure increase secondary to LV regional ischemia is the preceding PV total systolic integral (LA reservoir inflow).
Pulmonary venous reservoir and conduit inflow to the LA.
Unlike the LV, which fills during diastole and empties during systole, the LA fills during the reservoir (its diastolic) phase, ejects actively during the contraction phase and both fills and empties (passively) during the intermediate conduit phase.
During the LA reservoir phase, PV systolic flow into the LA cavity can be subdivided into an early and a late phase, as suggested by both the biphasic nature of the systolic PV flow pattern and the biphasic characteristics of the rate of LA area increase during filling (12,19). During the early reservoir phase, LA inflow is thought to be determined mainly by LA myocardial relaxation (3–5,19) which, by decreasing LA pressure (the x trough), accelerates PV flow and defines the PV early systolic wave (Fig. 4). In contrast, during the late reservoir phase, LA pressure and dimension increase in parallel (along a diastolic pressure to volume curve which defines, as for the LV, the LA stiffness characteristics) (12,20,21), and the relaxed LA myocardium is distended by PV inflow as the mitral annulus (cardiac base) is pulled towards the LV apex by LV longitudinal fiber contraction (12). Consequently, it has been suggested that systolic PV late inflow may result from the interplay of LA chamber stiffness (17,22,23), LV isovolumic contraction (24), LV systolic function (through the descent of the cardiac base) (3,5,6) or the upstream pressure (RV systolic pressure) transmitted through the pulmonary circulation (7). During the LA conduit phase, the LA empties into the LV during LV relaxation and simultaneously refills from the PVs. Consequently, LA physiology at this time has been described as completely passive (11) and the PV early diastolic wave compared with the transmitral early diastolic wave (1,6,9–11). However, the LA cavity during the preceding reservoir phase is stretched by both cardiac base descent (12) and PV systolic inflow, storing elastic energy (25), which could be returned during the conduit phase and, thus, influence PV early diastolic flow together with LV relaxation.
Conclusive evidence quantitating the determinants of PV systolic inflow is lacking. Furthermore, in contrast with our study, previous analyses (either transthoracic or transesophageal) have not separated the determinants of the early and late systolic PV flow waves (12). Using bivariate analysis, previous studies have related the early and late PV systolic waves to LA relaxation and LV contraction (5,6) and the early PV diastolic peak wave velocity and deceleration time to the early transmitral diastolic wave (9,10). However, multiple regression analysis may be more appropriate when numerous variables are expected to interact (and confound the analysis). Further, to be clinically meaningful, this analysis must consider more than a single baseline situation and account for the effects of changes that accompany LA loading changes. In the latter case, failure to account for between-subjects variability may lead to overestimation or underestimation of the effects of independent variables (18). We analyzed the determinants of systolic and diastolic forward PV flow by statistically controlling for a series of confounding factors in the face of changed loading conditions that accompany changes in heart rate and the presence or absence of ischemia: heart rate, LA preload (LA area before atrial contraction, or LA end-diastolic area) and afterload (LV end-diastolic pressure and chamber stiffness) (15), between-subjects variability. Of note, analysis of hemodynamic changes occurring during increased LA afterload (LV diastolic pressures) may exemplify changes occurring in acute coronary artery disease or dilated cardiomyopathy in man.
Determinants of pulmonary venous early systolic wave.
We previously demonstrated that PV early flow peak velocity and velocity-time integral are related to LA contraction and LA (cavity expansion during) relaxation and that the LA early reservoir area change is determined by LA relaxation (12). These findings point to a LA contraction-relaxation relation similar to the LV contraction-relaxation cycle (19,26) and relate the early PV flow wave to LA dimensional changes occurring during both LA contraction and relaxation, as previously suggested (5,6,8,12,19).
When a multivariate approach is used, only LA pressure modifications during LA relaxation can independently predict the early systolic wave (Table 1, Fig. 5), suggesting that LA relaxation is the main determinant of the PV early systolic wave (although the latter is also synchronous to LV isovolumic contraction outflow acceleration). Accordingly, the early systolic peak flow velocity occurred at the LA x pressure trough in our study (27). Our findings also suggest that Doppler PV flow indexes are related to changes in intracavitary pressure (8) (Fig. 5) better than to changes in LA dimensions, consistent with the fact that Doppler velocities are physically related to intracavitary pressure gradients (Bernoulli equation). Our findings agree with previous studies noting that Doppler venous inflow troughs and peaks were inversely related to peak and troughs of atrial pressure tracings (3,4,8,10,13). Further, our data show that the vis a tergo (the upstream component of LA inflow) does not significantly influence LA inflow during early reservoir.
Our data are consistent with previous Doppler transthoracic (1) and transesophageal (5,6,27) studies that have indirectly suggested that LA relaxation is the main determinant of the early LA inflow phase. Other studies havenot separately analyzed the two PV systolic waves (9,10,14,24,27) and, thus, could not (and did not) define a role for LA relaxation in determining PV systolic flow.
Determinants of pulmonary venous late systolic wave.
Our study shows that the LA end-reservoir maximum area, the LA pressure x trough (Fig. 5) and the RV systolic – LA peak v pressure difference (thus, both vis a tergo and a fronte) are the independent predictors of the PV late systolic flow wave. Consistent with the simplified Bernoulli equation and similar to the early reservoir phase, LA phasic pressure changes are an important determinant of the PV late systolic wave. Unlike the PV early systolic wave, the PV late systolic wave is also related to LA dimensions. The PV late systolic wave is synchronous with LA passive filling occurring during LA late reservoir (12) (Fig. 4). Because the mitral valve is closed, we expect a relation between Doppler velocity estimates of LA inflow and a cross-sectional estimate of LA expansion, assuming that Doppler PV velocities sampled from a single vein are proportional to total LA inflow.
Previous studies have proposed different determinants of the PV late systolic flow wave. As mentioned above, most studies have only analyzed total systolic PV flow (9–11,14,24,27), not considering that the PV early and late waves may have different determinants. Because only the highest PV systolic velocity was generally measured, the characteristics of the late systolic PV flow wave were de facto described (the highest velocity usually coinciding with the late systolic peak velocity). The only study that separately analyzed the PV early and late systolic waves suggested, based on indirect evidence (timing correspondence between the PV late flow wave and LV ejection), that the latter was originated by the systolic descent of the mitral anulus and its associated LA pressure decrease (5). Similarly, other studies have indicated either LA contraction and relaxation (1,6), LV systolic function (10) or both the systolic descent of the cardiac base (3,5,6) or cardiac output (9,11) as determinants of the systolic PV flow pattern. Though a study in patients during open heart surgery did find a positive bivariate relation between PV systolic peak velocity and LA compliance (calculated combining LA pressure and M-mode diameters between the LA x trough and peak v pressure points), this relation was not confirmed in a multivariate analysis (27).
A recent Doppler study (8) has reassessed the determinants of the Doppler PV flow pattern in terms of vis a tergo (7,8) as opposed to vis a fronte (1,4,13,28), indicating a predominant role for "upstream" RV stroke volume in determining systolic PV flow. These conclusions were based on the indirect findings that the systolic pressure wave in the PV segment nearest to the pulmonary capillary bed resembled a delayed pulmonary artery pressure wave and that respiratory pressure changes in the PV and artery were linked (8). In contrast, our study stresses the predominance of vis a fronte factors in determining PV systolic waves by providing direct quantitative data analyzed through a multivariate approach. It should, however, be noted that species-related factors may account for differences between studies. The ratio of systolic to total PV flow found in our pigs was greater than that found in dogs (8) and more similar to that found in human adults (29). The characteristics of the PV-LA pressure gradient (and the LA chamber diastolic characteristics) may be different in dogs compared with pigs or man.
Determinants of pulmonary venous total systolic velocity-time integral.
As for the PV early and late flow waves, LA pressure (peak v, which is related to LA stiffness) is an important determinant of the PV total systolic velocity-time integral (Fig. 5). However, the main determinant of the total systolic velocity-time integral is LV stroke volume. Thus, LV performance is the strongest factor related to PV systolic flow and, hence, LA reservoir function. Our present LA Doppler inflow findings are consistent with our previous LA dimensional (LA area changes) study that defined cardiac output and LA stiffness as the main determinants of LA reservoir function (12). Although significant in bivariate analysis using only the baseline data paced at 70 beats/min, the influence of RV systolic pressure on the total PV systolic velocity-time integral is not significant in the multivariate analysis, which obtains more data from each animal under a variety of experimental conditions. Altogether, these findings suggest that RV systole influences the PV flow pattern less than LV systole and LA chamber stiffness (4,8). Our results are consistent with previous studies that have reported, but not quantified, an inverse relationship between venous systolic inflow waves and atrial pressures during LA reservoir (3,4,8,10,13) and with studies that have correlated PV systolic inflow and cardiac output during load manipulation in patients with normal LV systolic function (9) or during monitoring of therapy in acute congestive heart failure (11).
A recent study indicated LA contraction as the main determinant of the PV systolic velocity-time integral (but no correlation data were reported) in the setting of acute LA load manipulation (14). However, LA contraction was defined as LA total dimension change which, in contrast, we defined (as do most authors [30–32]) as LA reservoir function. Even so, we did not find a relation between LA area change and PV systolic velocity-time integral during the reservoir phase.
Determinants of pulmonary venous early diastolic flow wave.
Our model suggests that the strongest determinant of the PV early diastolic wave during the LA conduit phase is the preceding PV total systolic integral and, thus, LA reservoir filling. Our finding contrasts with previous studies that have suggested, but not demonstrated, that LV relaxation is the main determinant of PV diastolic forward flow (9,11). This suggestion was based on the assumption that after mitral valve opening the blood is passively driven into the ventricle by a pressure gradient generated by LV relaxation and that the atrium must behave as a passive conduit as blood flows directly from the PVs into the ventricle. However, our results are supported by our recent finding in this same animal model that the LA pressure to area v loop is counterclockwise and, thus, that some energy must be produced by the atrium during conduit emptying (12). We speculated, in agreement with a previous study (25), that the stretching of the atrium by systolic PV inflow during LA reservoir would deliver elastic energy during early diastole to facilitate early diastolic LV inflow (12). Our present findings support our speculation by demonstrating that in our model LA reservoir is the main determinant of the PV early diastolic wave. Consequently, we hypothesize a preload dependency of the LA early conduit phase, resembling the Frank-Starling relationship previously demonstrated for the LA contraction phase (33). Further, it must be noted that in our model LA peak v pressure is a determinant of the PV systolic velocity-time integral. Consequently, LA peak v pressure also influences the PV early diastolic flow wave. Thus, our data are in agreement with previous evidence relating LA peak v pressure (as a substitute for LV to LA crossover pressure) to early diastolic flow velocities (34). Finally, our finding that the PV total systolic integral determines the ensuing PV early diastolic wave may seem discrepant with the common clinical finding of a "diastolic dominant" PV flow velocity pattern in the setting of LV restrictive filling physiology (11). However, our model—as stated—was not intended to produce LV failure and a major increase in LA pressure, as found in LV restrictive filling physiology. Thus, our findings should not be considered as an alternative to but as complementary to previous clinical findings.
LV regional ischemia, heart rate and pulmonary venous anterograde flow.
As previously reported by us, LV regional ischemia increases LA mean pressure and chamber stiffness and decreases LA reservoir function (secondary to reduced LV long axis shortening); consequently, PV late systolic peak velocity decreases (12). Although a direct relation between reduced PV early diastolic velocity-time integral and reduced transmitral early diastolic flow (12) during LV ischemia (secondary to prolonged LV relaxation) would be plausible—because both flows are simultaneous—our multiple regression analysis points to the preceding LA reservoir filling (PV total systolic integral) as the main determinant of the PV diastolic velocity-time integral.
Increasing heart rate to 90 beats/min decreased both LA (12) and PV pressures. The PV early diastolic flow wave decreased, whereas the systolic wave did not change. Again, the multivariate analysis did not confirm a cause-and-effect relation between the reduction of both the transmitral and PV early diastolic flow waves.
Relation between LA pressure changes and pulmonary venous anterograde flow.
Our study discloses an inverse relation between changes in LA peak v pressure and the PV systolic velocity-time integral (Table 1, Fig. 5). Previous authors have described a parallel increase in PV systolic velocities and LA pressure (9,13,14). This apparent discrepancy is easily explained by the different methods used to modify LA load and pressure. In contrast with previous studies that have increased LA pressure by volume loading (LA preload increase) (9,13,14), we have purposely increased LA pressures by increasing LV chamber stiffness and end-diastolic pressure (15) (LA afterload) through LV regional ischemia. Our model is based on LV acute regional ischemia of limited duration. It was not intended to create LV failure. Thus, the model is not immediately comparable—and should not be compared—to others that have analyzed acute or chronic LV failure. Our model finds its place in the "continuum" that relates intracavitary pressure and Doppler flow velocities—between normal physiology and marked increase in intracavitary pressures. Interestingly, our model of LA pressure increase may be close to the LA pathophysiologic changes occurring in man with acute coronary artery disease or mild congestive heart failure. Thus, we are aware that caution must be exercised when extrapolating conclusions directly from experimental studies (as our ischemia model in open pericardium pigs) to the clinical setting.
Conclusions.
Our Doppler analysis of PV reservoir inflow shows that the overall systolic flow pattern is determined by both LV systolic function and LA pressure (vis a fronte), whereas its early and late components reflect different determinants (in contrast with previous studies) (8,16) primarily related to vis a fronte. We also demonstrate that the determinants of PV inflow and of LA dimension changes (as previously described) (12) are similar during the early (LA relaxation) and different during the late reservoir phases (LV systolic function as opposed to LA intracavitary pressures). Finally, LA reservoir inflow appears to be a predictor of LA early conduit flow.
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Acknowledgments
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We thank Jim Stoughton for assistance with the experiments.
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Footnotes
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This work was supported by NHLBI Grant HL-25869. Dr. Barbier was a Research Fellow supported by a grant of the Centro Cardiologico Fondazione "I. Monzino," IRCCS, CNR, Milan, Italy.
1 Dr. Barbier’s current address is: Centro Cardiologico Fondazione "I. Monzino," IRCCS, CNR, via Parea 4, 20138 Milan, Italy. E-mail: pbar@iol.it. 
2 Dr. Solomon’s current address is: National Institutes of Health, Critical Care Medicine Dept, Building 10, Rm 7D43, 10 Center Drive, MSC 1662, Bethesda, Maryland 20892-1662. E-mail: ssolomon@cc.nih.gov.
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