INTRODUCTION

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A NUMBER OF STUDIES using Doppler echocardiography have revealed dramatic changes of the left ventricular (LV) intracavitary filling pattern in patients with LV dysfunction, and Doppler-derived indexes of intraventricular flow have been proposed as markers of diastolic dysfunction (1, 6, 14, 19). The clinical application and interpretation of these indexes, however, suffer from lack of understanding of the fundamental principles of LV intracavitary flow. As outlined by Yellin et al. (21), the physiology of intraventricular flow is complex and there is probably no simple relationship between LV function and the intraventricular flow field. To better understand intraventricular filling it is important to know more about the driving pressures for flow propagation. Studies in dog models have shown significant diastolic pressure gradients in early as well as late diastole (3, 4, 7, 10, 12, 17). The combination of ventricular imaging by color M-mode Doppler with measurement of intraventricular pressure gradients may provide further insight into the determinants of intraventricular flow.

The general objective of this study was to investigate mechanisms of LV intracavitary flow during rapid early diastolic filling. To this end we first characterized intraventricular pressure gradients and flow velocities in humans. In a group of patients with coronary artery disease and intact LV systolic function we observed that arrival of the early diastolic filling wave at the apex was associated with a substantial pressure gradient from LV apex (P_LVapex) to outflow tract (P_LVoutflow). Because of the constraints of a clinical study we did supplementary studies in a dog model. We were able to reproduce the intraventricular pressure gradients from the clinical study and thus could use the dog model to explore underlying mechanisms.

	METHODS

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Clinical Study

Patient population. The study population consisted of eight male patients aged between 42 and 66 yr (mean 51 yr) with stable angina pectoris referred for coronary angiography. Patients with previous myocardial infarction or valvular heart disease were excluded. Before the invasive study all patients underwent an echocardiographic examination that included measurements of transmitral blood flow velocities and mitral-apical filling pattern by color M-mode Doppler (19). All patients were in sinus rhythm, had normal resting electrocardiograms (ECG), and had mitral-to-apical filling patterns within normal limits (18).

Pressure measurements. A 7-F micromanometric catheter with two pressure sensors and a fluid lumen (model no. SSO-654, Millar Instruments, Houston, TX) was introduced via the left femoral artery and advanced into the LV as far as possible toward the apex. In case of ectopics the catheter position was slightly adjusted so that all measurements could be done during sinus rhythm. At the end the catheter had a small pigtail and proximal to this two pressure sensors with 5-cm spacing, as indicated in Fig. 1. Both micromanometers were calibrated before the study. To eliminate hydrostatic pressure differences the micromanometers were zero referenced to pressure measured via a fluid-filled lumen in the catheter (SensoNor, Horten, Norway). This adjustment was done during long diastasis after ventricular extrasystoles so that the pressure traces could be superimposed.

View larger version (20K): [in this window] [in a new window]   Fig. 1.   Placement of pressure sensors. A: clinical study. Sensors were located in left ventricular (LV) outflow tract and in apical region. B: dog study. In addition to pressure sensors in LV outflow tract and in apical region, there was a sensor in left atrium (LA).

Doppler echocardiography. Doppler echocardiographic data were recorded by a Vingmed CFM 700 cardiac ultrasound machine (Vingmed Sound, Horten, Norway). Transthoracic measurements were performed with the patient tilted slightly to the left. From the apical long-axis view and guided by the two-dimensional color flow map we positioned the color M-mode cursor along the mitral-apical axis (inflow tract) and recorded simultaneous blood flow velocities and pressures. We then positioned the cursor along the apical-aortic axis (outflow tract) and again recorded flow velocities and pressures. The velocity filter was set in the range of 8-12 cm/s. The pressure data, Doppler velocity data, and ECG data were synchronized by an electrical pulse that was superimposed on the ECG signal and fed into both computers. The digital color velocity data and ECG data were transferred to an external computer (Macintosh IIci, Apple Computer) and were analyzed as described by Stugaard et al. (19), using the software program EchoDisp (Vingmed Sound).

Experimental Study

Animal preparation. Five dogs of either sex and average body weight of 22 kg were given thiopental sodium (25 mg/kg body wt) and morphine (100 mg iv) followed by infusion of morphine (50-100 mg/h iv) and pentobarbital sodium (50 mg iv) every 1.5 h. The animals were artificially ventilated through a cuffed endotracheal tube using room air with 20-40% oxygen. Body temperature was maintained by a heating blanket. A limb-lead ECG was monitored.

Pressure measurements. A stiff, fluid-filled 7-F catheter was introduced via a femoral artery and placed in the aortic arch for monitoring aortic pressure. A miniature pressure transducer (Konigsberg Instruments, Pasadena, CA) was inserted into the LV cavity through a stab wound in the apical dimple and was pulled carefully back toward the endocardium and secured by a suture. A 5-F micromanometer-tipped catheter (model MPC-500, Millar Instruments) was introduced into the LV via a carotid artery and then was pulled back until we could see the impact from the aortic valve on the pressure trace. The catheter then was advanced ~5 mm below the aortic valve so that it was located in the LV outflow tract. In one dog we instead measured P_LVapex by a 5-F micromanometer-tipped catheter introduced from the left carotid artery and then used fluoroscopy to verify position in the LV apex. In this dog the micromanometer in the LV outflow tract was introduced through the apical region and was first advanced into the aorta. It was then pulled back slowly until we could see the impact from the aortic valve on the pressure trace, and it was pulled ~5 mm further down into the outflow tract. Via a pulmonary vein a 7-F micromanometer-tipped catheter with fluid lumen (model SPC-474A, Millar Instruments) was placed in the left atrium (LA).

Sonomicrometry. Three pairs of ultrasonic crystals were implanted in the endocardium of the LV to measure the equatorial anteroposterior (D_ap), septum-free wall (D_sfw) and apex-base (long axis; D_la) diameters and were connected to a sonomicrometer (Triton Technology, San Diego, CA).

Doppler echocardiography. Doppler echocardiography data were recorded by a Vingmed CFM 700 cardiac ultrasound machine (Vingmed Sound). Because the dog was placed in the left supine position, the heart was close to the chest wall and we obtained good images from the apical view using a transthoracic approach. Color M-mode Doppler was used to record flow velocities along the mitral-apical axis and the apical-aortic axis. Velocity and pressure data were obtained simultaneously. Data were recorded and processed in a fashion similar to that described for the clinical study.

Experimental protocol. Recordings were first obtained during baseline. We then inflated both caval occluders, and recordings were performed during progressive reduction in LV filling. After release of the caval constriction the animals were allowed to stabilize, and we then infused saline intravenously, aiming at increasing LV end-diastolic pressure to ~15 mmHg.

Data Analysis

Pressure measurements. LV peak systolic pressure, minimum diastolic pressure, end-diastolic pressure, and the time derivative of pressure (dP/dt) were calculated. The time course of the fall in P_LV from minimum dP/dt to P_LV 5 mmHg above end-diastolic pressure was characterized by the time constant () of an assumed exponential decay to zero pressure (20). In each of the patients we obtained curve fits with r values exceeding 0.99, and in each of the dog experiments r values exceeded 0.98. We also calculated  by the derivative method (5), but the curve fits were not as good. Therefore, the former method was used in the further analysis.

Calculation of pressure gradients. Because early diastolic flow along the apex-outflow tract axis was directed toward the outflow tract, we calculated the intraventricular pressure gradient as P_LVapex  P_LVoutflow. The following gradients and pressures were calculated: peak negative early diastolic P_LVapex  P_LVoutflow, peak positive early diastolic P_LVapex  P_LVoutflow, peak positive late diastolic P_LVapex  P_LVoutflow, peak positive systolic P_LVapex  P_LVoutflow, peak negative systolic P_LVapex  P_LVoutflow, peak positive LA pressure (P_LA)  P_LVapex, peak negative P_LA  P_LVapex, and first diastolic P_LA-P_LV crossover.

Sonomicrometry. In the dog study LV volume (V_lv) was calculated as a general ellipsoid using the equation V_lv = (D_ap · D_sfw · D_la · )/6. Stroke volume was calculated from the LV volume signal, and transmitral filling was calculated as the time derivative of LV volume in diastole (dV/dt) (2). We estimated peak early and peak atrial-induced transmitral filling from dV/dt.

Statistical analysis. The reported values are the mean value of three beats recorded during quiet respiration in the patients and with the respirator off in the dogs. During caval constriction we used a single beat at maximum constriction. Data are reported as means ± SE. Regional pressures were compared using Student's t-test for paired samples. Values before and during each intervention were compared using a repeated-measures ANOVA followed by a Student-Newman-Keuls test to isolate treatment effects. Regression analysis was done according to Glantz and Slinker (8) with a multiple-regression model including dummy variables to account for between-individual differences. A probability value of <0.05 was considered significant.

	RESULTS

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Intraventricular Pressure Gradients in Humans

View larger version (27K): [in this window] [in a new window]   Fig. 2.   Intraventricular pressures, pressure gradients and time derivative of pressure (dP/dt) in a representative patient. During most of early diastole and during late diastole (atrial contraction) LV pressure (PLV) in apical region (PLVapex) exceeds pressure in outflow tract (PLVoutflow). Similarly, during early systole there is a positive pressure gradient from apex to outflow tract. During late systole and during first part of isovolumic relaxation period there is a negative pressure gradient.

In late diastole, during atrial contraction, there was also a positive pressure gradient from the apex to the outflow tract; its peak value was 1.8 ± 0.2 mmHg.

During early systole there was a positive gradient of 3.7 ± 0.4 mmHg between apex and outflow tract (Fig. 2). During late systole there was a negative gradient with a peak value of 3.9 ± 0.5 mmHg, occurring 20 ± 2 ms before peak negative dP/dt. This negative gradient continued into the first part of the isovolumic relaxation period. Figure 3 shows pressure data from individual patients, and Table 1 summarizes hemodynamic variables in the patients.

View larger version (32K): [in this window] [in a new window]   Fig. 3.   Individual patients (1-4, 6-8) showing diastolic PLVapex and PLVoutflow (patient 5 is displayed in Fig. 2). Magnitude of early diastolic intraventricular pressure gradient varies considerably.

Intraventricular Pressure Gradients in Dog Model

View larger version (30K): [in this window] [in a new window]   Fig. 4.   Top: intraventricular pressures and PLA in a representative dog experiment. Bottom: transmitral gradient (PLA  PLVapex) and LV apex-outflow tract gradient (PLVapex  PLVoutflow). Recordings shown made during baseline (left), during caval constriction (middle), and after intravenous volume loading (right). Note that there is a gradient between apex and outflow tract similar to clinical findings. Peak early diastolic gradient is markedly reduced by caval constriction and is increased by volume loading.

In one dog we moved the pressure sensor in the LV outflow tract toward the apex in steps of 5 mm and could demonstrate a progressive decrease in the apex-to-outflow tract pressure difference.

Intraventricular Pressure Gradients and Relationship to Filling Velocities and LV Function in Clinical Study

View larger version (63K): [in this window] [in a new window]   Fig. 5.   Simultaneous recording of LV intracavitary flow velocity and pressures. For this recording, color M-mode cursor was positioned so that LV inflow and outflow velocities were visualized on same image.

View larger version (19K): [in this window] [in a new window]   Fig. 6.   Simultaneous recording of LV flow velocity 2 cm below aortic valve, PLVoutflow, and PLVapex  PLVoutflow.

The peak early diastolic apex-outflow tract pressure gradient correlated with peak early flow velocity measured along the apex-to-outflow tract axis (r = 0.75, P < 0.05) and with peak early velocity along the mitral-apical axis (r = 0.87, P < 0.01).

The apex-to-outflow tract pressure gradient correlated significantly with the LV ejection fraction (r = 0.79, P < 0.03) and with  (r = 0.71, P < 0.05). The value of  was similar in the LV apex and in the outflow tract (Table 1). However, peak negative dP/dt occurred slightly earlier in the outflow tract than in the apex (mean difference 6 ± 1 ms; P < 0.001).

Effects of Changes in LV Loading on Intraventricular Pressure Gradients in Dog Model

When regression analysis was performed on pooled data from recordings taken during changes in LV loading, the apex-to-ouflow tract pressure gradient correlated strongly with peak transmitral blood flow (r = 0.95, P < 0.001) and with stroke volume (r = 0.97, P < 0.001; Fig. 7). Furthermore, the gradient correlated positively with end-systolic volume (r = 0.92, P < 0.003), i.e., when LV end-systolic volume decreased, there was a decrease in the apex-outflow tract pressure gradient.

View larger version (29K): [in this window] [in a new window]   Fig. 7.   Relationship between early diastolic intraventricular pressure gradient and transmitral flow and stroke volume in experimental study. Top: PLVapex  PLVoutflow vs. maximum early rapid transmitral filling (time derivative of LV volume; dV/dt). Bottom: PLVapex  PLVoutflow vs. stroke volume. Pooled data from 5 dogs during baseline, during caval constriction, and after intravenous volume loading.

	DISCUSSION

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In a group of coronary patients with normal ejection fraction, early diastolic mitral-to-apical flow propagation and subsequent redistribution of flow toward the LV outflow tract were associated with a substantial intraventricular pressure gradient. In a dog model, which allowed even more precise placement of the pressure sensors, we were able to reproduce the apex-to-outflow tract pressure gradient. In this model we also demonstrated a marked increase in peak gradient during volume loading and a marked decrease during reduced LV filling by caval constriction, and the intraventricular pressure gradient correlated strongly with peak rate of transmitral filling and with stroke volume. The gradient thus appears to reflect mass and velocity of global LV filling. The pressure gradient also correlated with peak apex-outflow tract velocities and therefore may play a role in the redistribution of the early filling wave toward the LV outflow region.

The present observations may seem to be in conflict with the studies of Courtois et al. (3, 4) and other previous studies in dogs (7, 10) that reported an early diastolic gradient from base to apex with minimum pressure in the apical region. However, the mitral-apical gradient in the studies of Courtois et al. (3, 4) was observed during very early diastole when LV apical pressure was decreasing, whereas in the present study the peak apex-outflow tract gradient in the dog model was observed somewhat later, 48 ± 2 ms after apical pressure nadir. We did additional measurements with a catheter that was introduced from the LA and with the sensor in the immediate submitral region, i.e., in the inflow tract. Figure 8 shows simultaneous pressures from this catheter and the apical sensor. We then confirmed the findings of Courtois et al. (3) by showing a progressive pressure drop from the LA to the submitral region and the apex. Therefore, the apparent inconsistency between the present study and previous work can be attributed to different transducer placement. Courtois et al. (4) and Nikolic et al. (13) seemed to have the basal pressure transducer closer to the LV inflow tract than in the present study.

View larger version (15K): [in this window] [in a new window]   Fig. 8.   Recordings from a dog experiment.: Top: PLA, PLVapex, and PLV recorded in submitral region (PLVsubmitral). Bottom: LV volume measured by sonomicrometry.

Others have suggested that the base-apical pressure gradient at onset of filling is generated by diastolic suction (4, 13). The pressure gradient from apex to outflow tract observed in the present study, however, is opposite in direction to that described along the inflow tract in the previous studies, and it occurred later in diastole. It is probably not a marker of diastolic suction but is related to intraventricular propagation of the early transmitral flow pulse and will be present regardless whether that flow is driven by suction or by the LA pressure head. This interpretation is supported by a very strong correlation to peak rate of early transmitral filling over a wide range of filling pressures. Furthermore, the finding of a similar although smaller pressure gradient during atrial contraction is consistent with this notion.

Similar to Pasipoularides et al. (16). we observed a systolic gradient between the LV apex and the subaortic area. Furthermore, we recorded a negative pressure gradient in late systole, and this gradient persisted into the isovolumic relaxation period. In most patients and in the dog model, there was a minor gradient directed from LV outflow tract to apex at onset of mitral-apical filling. The physiological significance of this gradient is unclear.

Limitations

Most of the patients in the present study had coronary heart disease, and although LV ejection fraction was normal, we cannot exclude some impairment of systolic function. All patients had normal mitral-apical flow propagation as judged by color M-mode Doppler (18). The fact that the patients were taking various cardiac medications may have influenced the gradient. Therefore, the absolute magnitude of the intraventricular gradient may not be representative for normal humans.

Because of the pigtail shape of the LV catheter in the clinical study, the distal pressure sensor was not at the most distal portion of the apex. In the dog experiments, however, the transducer was inserted through the apical dimple, and accurate position at distal apex was confirmed during autopsy.

In conclusion, during early LV filling there was a substantial pressure gradient between the apex and the outflow tract. The pressure gradient was sensitive to changes in preload and correlated strongly with peak early transmitral flow. The significance of this gradient for intraventricular flow propagation in the normal and the diseased heart remains to be determined.