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CLINICAL STUDY

Left ventricular outflow tract mean systolic acceleration as a surrogatefor the slope of the left ventricular end-systolic pressure-volume relationship

Fabrice Bauer, MD^*, Michael Jones, MD, Takahiro Shiota, MD, FACC^*,*, Michael S. Firstenberg, MD^*, Jian Xin Qin, MD^*, Hiroyuki Tsujino, BSc^*, Yong Jin Kim, MD^*, Marta Sitges, MD^*, Lisa A. Cardon, RDCS^*, Arthur D. Zetts and James D. Thomas, MD, FACC^*

^* Cleveland Clinic Foundation, Cleveland, Ohio, USA
National Heart, Lung, and Blood Institute of Health, Bethesda, Maryland, USA

Manuscript received November 8, 2001; revised manuscript received May 6, 2002, accepted June 27, 2002.

^* Reprint requests and correspondence: Dr. Takahiro Shiota, Department of Cardiology, Desk F15, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, Ohio 44195, USA.
Shiotat{at}ccf.org

	Abstract

Top Abstract Methods Results Discussion APPENDIX References

 
OBJECTIVES: The goal of this study was to analyze left ventricular outflow tract systolic acceleration (LVOT_Acc) during alterations in left ventricular (LV) contractility and LV filling.

BACKGROUND: Most indexes described to quantify LV systolic function, such as LV ejection fraction and cardiac output, are dependent on loading conditions.

METHODS: In 18 sheep (4 normal, 6 with aortic regurgitation, and 8 with old myocardial infarction), blood flow velocities through the LVOT were recorded using conventional pulsed Doppler. The LVOT_Acc was calculated as the aortic peak velocity divided by the time to peak flow; LVOT_Acc was compared with LV maximal elastance (E_m) acquired by conductance catheter under different loading conditions, including volume and pressure overload during an acute coronary occlusion (n = 10). In addition, a clinically validated lumped-parameter numerical model of the cardiovascular system was used to support our findings.

RESULTS: Left ventricular E_m and LVOT_Acc decreased during ischemia (1.67 ± 0.67 mm Hg·ml^–1 before vs. 0.93 ± 0.41 mm Hg·ml^–1 during acute coronary occlusion [p < 0.05] and 7.9 ± 3.1 m·s^–2 before vs. 4.4 ± 1.0 m·s^–2 during coronary occlusion [p < 0.05], respectively). Left ventricular outflow tract systolic acceleration showed a strong linear correlation with LV E_m (y = 3.84x + 1.87, r = 0.85, p < 0.001). Similar findings were obtained with the numerical modeling, which demonstrated a strong correlation between predicted and actual LV E_m (predicted = 0.98 [actual] –0.01, r = 0.86). By analysis of variance, there was no statistically significant difference in LVOT_Acc under different loading conditions.

CONCLUSIONS: For a variety of hemodynamic conditions, LVOT_Acc was linearly related to the LV contractility index LV E_m and was independent of loading conditions. These findings were consistent with numerical modeling. Thus, this Doppler index may serve as a good noninvasive index of LV contractility.

Abbreviations and Acronyms   ANOVA   analysis of variance   EF   ejection fraction   Em   maximal elastance   LV   left ventricle/ventricular   LVOT   left ventricular outflow tract   LVOTAcc   left ventricular outflow tract systolic acceleration   MI   myocardial infarction   PV   peak aortic flow velocity   t-PV   time to peak velocity   t-PVcor   the heart rate-corrected time of time to peak velocity

Ascending aortic blood flow velocities and acceleration have been previously reported to be sensitive to inotropic stimulation and little affected by changes in loading conditions (3,4). Accordingly, this study is aimed at analyzing simultaneously the LV E_m and the blood flow acceleration in the left ventricular outflow tract (LVOT) under a variety of hemodynamic conditions, including changes in preload, afterload, and contractility.

	Methods

Top Abstract Methods Results Discussion APPENDIX References

 
Preparation.   Eighteen juvenile sheep were used in this study. The study protocol was approved by the Animal Care and Use Committee of the National Heart, Lung, and Blood Institute. Details of anesthetic management and surgical procedures have been previously reported (5). Chronic aortic regurgitation had been surgically created six months earlier in six sheep by incising the free edge of the right coronary or the noncoronary cusp. The left anterior descending diagonal coronary artery had been occluded six months earlier, resulting in chronic myocardial infarction (MI) in eight sheep. Four sheep had normal hearts.

Twenty-six weeks later, general anesthesia was induced using intravenous pentobarbital (30 to 50 mg/kg). The sheep were intubated and ventilated. Anesthesia was maintained by using isoflurane with oxygen. A median sternotomy was performed. Left ventricular pressure was measured by a catheter-tipped high-fidelity micromanometer (Model SPC-350, Millar Instruments, Houston, Texas) introduced transmurally. Another catheter-tipped micromanometer introduced from the carotid artery measured ascending aortic pressure. The catheters were interfaced with a physiologic paper recorder (ES 2000, Gould Inc., Cleveland, Ohio).

Conductance catheter
Left ventricular pressure-volume loops were determined by a conductance catheter (SPC 560, Millar instruments Inc., Houston, Texas) inserted via the LV apex. This catheter was connected to a stimulator-microprocessor (Leycom, CardioDynamics, Zoelermeer, the Netherlands) to display a pressure-volume signal. Electromagnetic flow probes (Model EP455, Carolina Medical Electronics Inc., King, North Carolina) were placed around the aorta and pulmonary artery. The conductance volume signal was calibrated against the stroke volume derived by the aortic electromagnetic flow probe. A snare was placed around the inferior vena cava.

Protocol
To analyze the relationship between E_m and left ventricular outflow tract systolic acceleration (LVOT_Acc), five different hemodynamic stages were produced for each sheep as follows. Stage 1 was baseline. Five hundred milliliters of whole blood were then transfused over 30 min (stage 2) in order to increase the preload. Angiotensin II was infused to increase the afterload (stage 3), whereas nitroprusside was administered to decrease both preload and the afterload (stage 4). Thereafter, the midportion of the left anterior descending coronary artery or the proximal left circumflex coronary artery was occluded to induce acute regional LV ischemia (stage 5). For each stage the hemodynamic state was stabilized for 15 min. Ventilation was suspended during each measurement.

Echocardiography
Echocardiographic Doppler acquisition was performed on a Toshiba ultrasound machine (PowerVision, Toshiba Medical System, Tokyo, Japan) equipped with a 3.7-MHz transducer. Hearts were scanned from the apical four-chamber window, using a standoff between the epicardium and the surface of the probe. The electrocardiogram was simultaneously acquired and displayed on the screen. The ultrasound beam was positioned in the LVOT, parallel to the aortic flow. To limit measurement errors due to a skewed peak velocity profile (6), the sample volume was placed 1 cm below the aortic valve, in the middle of the LVOT, where the optimal Doppler spectrum for cardiac output is usually recorded. The LVOT was interrogated in the pulsed-Doppler mode. Optimal Doppler gain was adjusted to display a complete blood flow velocity spectral envelope with minimal noise/signal ratio. The Doppler signal was recorded on a high-fidelity videocassette recorder (Model SVO-9500MD, Sony, Tokyo, Japan) interfaced with the ultrasound machine, for offline analysis.

Mathematical modeling
Using a previously described mathematical model of the cardiovascular system (7), the relationship between LV Em and Doppler LVOTAcc was also examined to verify experimental results. Briefly, our model uses 24 first-order differential equations to simulate pressure, volume, and flow throughout the heart and vessels, implemented in the LabView programming environment (National Instruments, Austin, Texas) on a 500 MHz Pentium III based computer. This model has been previously validated clinically in described complex intracardiac fluid dynamics and pressure-volume relationships (8,9). For 45 different permutations modeled by varying LV E_m (1.0 to 7.0 mm Hg·ml^–1) and independently varying either preload or afterload, instantaneous LV and LVOT pressures, volumes, and velocities were derived in 5-ms intervals for analysis. The LVOT_Acc was determined from the velocity profiles using methods similar to those previously described for the animal data (Appendix).

Data measurements
We measured the peak positive of the first time derivative of the left ventricular pressure (dP/dt) (maximal dP/dt [dP/dtmax]). We determined LV end-diastolic pressure when positive dP/dt first exceeded 200 mm Hg·ml^–1 and LV end-systolic pressure at the upper point of the LV pressure curve. Aortic pressure was measured as the systolic peak and diastolic trough. Left ventricular stroke volume was calculated as the flow-time integral recorded from the aortic electromagnetic flow probe. Left ventricular cardiac output was LV stroke volume x heart rate.

The ventricular end-systolic pressure-volume relationship was derived from a set of multiple and variably loaded pressure-volume loops generated by occlusion of the inferior vena cava. Data were digitally stored for offline analysis. Points of LV end-systolic pressure-volume were recorded during at least 12 loops. Data were fit by linear regression analysis, and the calculated slope was the LV E_m (Fig. 1).

View larger version (29K): [in this window] [in a new window]   Figure 1 An example of left ventricular (LV) pressure-volume relationship recording from an invasive conductance catheter (left) and LV outflow tract pulsed-wave Doppler recording from the apical view. Left ventricular outflow tract acceleration was calculated as peak velocity ÷ time to peak velocity (right).

Statistical analysis
Data are presented as mean ± SD. Changes in invasive and noninvasive parameters under variable hemodynamic conditions were compared with the use of an analysis of variance (ANOVA). To increase the power of our index, we adjusted LVOT_Acc for LV E_m (covariate) using an analysis of covariance. We initially tested the linear relationship between LVOT_Acc and LV E_m for each stage and in each cardiac group separately by a least-squares method followed by a one-way ANOVA for statistical significance. Then we investigated the homogeneity of regression to detect an interaction. For p > 0.05, we accepted the homogeneity of slopes, and a standard one-way covariance was indicated. For the overall study, correlation between LVOT_Acc and E_m were investigated by linear regression analysis. A p value of <0.05 was considered to be significant. To determine the intra- and interobserver variability for the LVOT_Acc and for the LV E_m measurements, 12 random data set were analyzed by one observer on two different days and by two independent observers.

	Results

Top Abstract Methods Results Discussion APPENDIX References

 
LV systolic and diastolic function at baseline.   At baseline, the three groups had similar heart rates and mean aortic pressures (Table 1). Left ventricular ejection fractions (EFs) were significantly lower in animals with chronic MI than those with aortic regurgitation or normal hearts. The aortic regurgitation group had higher cardiac outputs than the other groups. Left ventricular peak +dP/dt was significantly smaller in animals with chronic MI than the other groups. Left ventricular E_m was significantly lower in animals with chronic MI and aortic regurgitation than in normal sheep.

The LVOT_Acc was insensitive to both preload and afterload alteration. However, LVOT_Acc showed a tendency to be higher during angiotensin II infusion. There was a definite change in the LVOT_Acc after acute coronary occlusion as compared with the other stages (p < 0.05). When a one-way analysis of covariance was performed, we did not detect any statistical difference between LVOT_Acc and LV E_m in the four different stages (p = 0.06), indicating that LVOT_Acc was load-independent. However, statistical significance was attained for the three different groups (p = 0.002), confirming that LVOT_Acc was influenced by different cardiac diseases.

Correlation between LVOT_Acc and E_m
An example of LVOT_Acc and LV E_m under different hemodynamic conditions is shown in Figure 2. The LVOT_Acc was linearly related to LV E_m (y = 3.84x + 1.87, r = 0.85, p < 0.001) (Fig. 3).

View larger version (40K): [in this window] [in a new window]   Figure 2 An example of left ventricular pressure-volume relationship (top), left ventricular outflow tract (LVOT) velocity (middle), and hemodynamic flow velocity data with numerical simulation modeling (bottom) for a sheep with chronic myocardial infarction at baseline, after blood infusion, after angiotensin infusion, after nitroprusside infusion, and during acute coronary occlusion.

View larger version (18K): [in this window] [in a new window]   Figure 3 Comparison between left ventricular (LV) outflow tract acceleration (LVOTAcc) (y axis) calculated from peak aortic flow velocity/time to peak velocity and LV maximal elastance (Em) from pressure-volume loops (x-axis) in 82 hemodynamic conditions. Solid triangles = during change in loading conditions; open triangles = during acute coronary occlusion.

Model of LVOT_Acc
For the 45 conditions simulated, LVOT_Acc ranged from 4.6 to 28.5 cm·s^–2. Similar to the animal data, there was a strong linear relationship between modeled E_m and LVOT_Acc (LVOT_Acc = 3.91[LV E_m] + 2.25; r = 0.94, p < 0.001). Furthermore, when the equation relating E_m to LVOT_Acc was used to predict E_m from the animal LVOT_Acc measurements, a linear relationship was observed between the observed and expected E_m (LV E_m expected = 0.98, LV E_m observed –0.01, r = 0.86, p < 0.001) (Fig. 4).

View larger version (16K): [in this window] [in a new window]   Figure 4 Comparison between left ventricular (LV) maximal elastance (Em) calculated from predicted LV outflow tract systolic acceleration (y axis) and actual pressure-volume loops (x axis) in 82 hemodynamic conditions.

	Discussion

Top Abstract Methods Results Discussion APPENDIX References

 
This study demonstrates that LVOT_Acc, an index of LV contractility independent of loading conditions, predicted alterations in LV systolic function, whereas conventional parameters failed to detect LV systolic impairment.

Previous studies about LV E_m.   A major limitation in assessing LV systolic function is the load-dependence of cardiac output, peak positive dP/dt, and EF. In the late 1970s, Sagawa et al. (1) described the LV end-systolic pressure-volume relationship over a wide range of end-systolic points, demonstrating that the slope of the end-systolic pressure-volume relationship (LV E_m) was linear, relatively insensitive to cardiac loading, and varied significantly in response to change in LV contractility. Therefore, LV E_m was considered to be the most reliable index of LV contractility. However, this index can be only obtained using sophisticated invasive procedures, including a pressure-volume catheter along with an abrupt change in preload or afterload. Therefore, its clinical use is limited.

Being aware of the advantages of measuring LV E_m, several authors attempted to simplify its calculation. The simplest method, reported by Little (11), was to calculate the ratio of end-systolic pressure to end-systolic volume. This simplified equation assumes constant zero pressure and volume intercepts. This is problematic because for a similar LV end-systolic pressure and volume ratio the volume intercept varies depending on the cardiac abnormality (12). Another approach was to calculate LV E_m as LV peak isovolumetric pressure – end-systolic pressure ÷ LV stroke volume. Igarashi et al. (13) and Takeuchi et al. (14) validated this method in normal hearts using the actual or an estimated LV peak isovolumetric pressure. However, when applied to a variety of cardiac abnormalities, the correlation between actual LV E_m and estimated LV E_m was weak because the cosine function-derived LV peak isovolumetric pressure was not applicable to dilated hearts (15). The last simplified method to calculate LV E_m was described by Senzaki et al (15). During early contraction the normalized time-varying elastance curve of the LV is similar among several underlying cardiac abnormalities and can be integrated in a complex equation in combination with LV end-systolic volume, LV end-diastolic volume, and aortic pressure to determine LV E_m. However, despite rigorous efforts to simplify LV E_m measurement, no individual method is applicable to all cardiac conditions and free of complicating factors or invasive procedure. Therefore, they have not seen widespread use in routine clinical settings.

Aortic blood flow acceleration
Despite some limitations, Doppler ultrasound recording of blood flow velocity, in the LVOT, ascending aorta, or descending aorta is well-validated to measure and to detect changes in cardiac output (16,17). Additional information such as peak velocity and acceleration can be obtained from aortic blood flow velocity. Noble et al. (18) first described and demonstrated invasively using a catheter-tipped velocity probe that the maximal acceleration of blood into the ascending aorta was sensitive to inotropic state and relatively insensitive to the loading conditions of the heart. Similar results were reported by Bennett et al. (3) using noninvasive Doppler ultrasound measurement of the ascending blood flow velocities in normals and later by Mehta et al. (19) in patients with chronic MIs. A limitation of measuring the maximal acceleration of the blood flow velocity is the need to calculate the first differential of velocity. This cannot be done routinely. Because a good correlation exists between peak and mean aortic blood flow acceleration (20), Wallmeyer et al. (4) calculated the mean acceleration of the ascending aortic blood flow velocity as the ratio of PV to t-PV flow. They reported that ascending aortic blood flow mean acceleration was significantly affected by inotropic alteration in dogs. Furthermore, Singer et al. (21) established that aortic blood flow mean acceleration was variably affected by alterations in loading condition.

In the present study, the forward blood flow mean acceleration was measured in a new location, that is, the LVOT. Consistent changes were seen in the Doppler-determined LVOT blood flow mean acceleration with changing LV contractility. However, despite a tendency for the Doppler LVOT blood flow mean acceleration to be higher during blood infusion, angiotensin infusion, and nitroprusside infusion, it was not significantly so. In addition, because there was a linear relationship between LV E_m and LVOT blood flow mean acceleration, LVOT blood flow mean acceleration can be used as a surrogate for LV E_m. Further validation of our experimental results was obtained through the numerical simulation of a wide range of physiologic conditions, which confirmed the linear relationship between the LV E_m and LVOT_Acc. Doppler-determined LVOT blood flow mean acceleration also reflects acute and chronic changes in the LV contractility. Interestingly, in animals with aortic regurgitation, LV systolic dysfunction was present as indicated by both lower LV E_m and lower LVOT blood flow mean acceleration despite good LV EF and cardiac output. Sabbah et al. (22) reported a close correlation between the ascending blood flow maximal acceleration and the LV EF. However, they did not explore this index in animals with potential LV dysfunction and normal LV EF such as found with aortic regurgitation or high-output heart failure.

Study limitations
The most important technical problem encountered in measuring the LVOT_Acc is difficulty in correctly identifying the onset and the peak of the blood flow velocity spectrum. Due to this technical limitation, Wallmeyer et al. (4) reported an LVOT_Acc mean difference between observers of 16.8%. As a second limitation, LVOT_Acc was not tested in the presence of turbulent flow in the outflow tract. It is unlikely that LVOT_Acc is applicable in patients with aortic stenosis or other types of LVOT obstruction. A third limitation relates to the velocity profile in the LVOT. In the present study, blood flow velocities were interrogated in the center of the LVOT. However, from previous studies we know that the blood flow velocity profile is skewed (6). The highest blood flow velocities are recorded near the septum and the anterior wall. As a direct function of velocity, LVOT mean acceleration should be affected by the site of blood flow interrogation, leading to a different relationship between LVOT_Acc and LV E_m. For consistency, reproducibility, and repeatability, care must be taken to measure LVOT_Acc at the same location. By extension, blood flow velocities are also affected by age. However, because the time to peak flow has not been explored in the elderly, age effects on LVOT_Acc are unknown.

Clinical implications
The LVOT_Acc reflects the LV contractility represented by LV E_m. It has numerous advantages over the measurement of the LV pressure-volume relationship. It is noninvasive and easily and quickly measurable. It may be preferred when LV EF and cardiac output fail to detect LV dysfunction such as in patients with aortic regurgitation or high-output heart failure. In contrast with studies by Bennett et al. (23), which demonstrated a close relationship between aortic peak flow acceleration and EF in patients with ischemic heart disease, we found a weak correlation between these two parameters (r = 0.43). Similarly, cardiac output was not related to LVOT_Acc (r = 0.35). However, we found a good correlation between LVOT_Acc and LV +dP/dt, another index of LV systolic function (r = 0.62).

Measuring the time-course of LVOT_Acc could be informative for surgical and medical decision-making. To date, LV EF is one of the most employed parameters used to follow patients with heart disease. However, it is well known that LV EF is dependent on loading conditions. Therefore, LVOT_Acc, which was independent of loading conditions, could be used to detect LV dysfunction in order to initiate therapy and to make serial evaluations of LV function after therapeutic interventions. Last, correlating LVOT_Acc and the prognosis of disease would certainly be a useful application.

Conclusions
Under varied cardiac conditions, LVOT_Acc was linearly related to LV E_m, reflected acute and chronic changes in LV E_m, and was independent of loading conditions. Thus, this Doppler-determined index may serve as a good noninvasive index of LV contractility.

	APPENDIX

Top Abstract Methods Results Discussion APPENDIX References

 
Numerical modeling was based upon previous research describing the mathematical relationships of fluid propagation through the cardiac chambers during both systole and diastole. In the LabView (National Instruments, Austin, Texas) programming environment we used, the lumped parameter, closed-loop model consisted of 24 first-order differential equations. These iteratively solved equations yield instantaneous (5-ms intervals) pressures (Equation 1), volumes (Equation 2), and flows (Equation 3) through the cardiovascular system (four chambers, pulmonary and systemic arterial and venous systems) across each of the four valves. A linear pressure-volume relationship and a constant compliance is used for the atrial, pulmonary, and systemic systems; for the ventricles, a linear pressure-volume relationship was used for systole, whereas diastole was modeled with a rising monoexponential function above and a negative exponential equation below an equilibrium volume. Experimentally obtained and clinically verified values for left atrial and ventricular systolic and diastolic parameters were used as constants (7). Results of the derived left ventricular hemodynamic data are summarized below.

(1)

(2)

(3)

C = compliance; i = chamber node; j = flow node; m = inertial term; P = pressure; Q = flow; r = resistance term; t = time; V = volume (ml).

Summary of Simulation Data of Hemodynamic Parameters

Min Max Ave SD LV end-systolic elastance 1.00 7.00 Systemic pressures (mm Hg) Mean 35.27 143.63 75.58 24.23 Systolic 43.41 161.50 90.99 26.73 Diastolic 27.56 123.68 59.81 21.45 LV EDP (mm Hg) 4.59 41.48 17.69 8.06 LV stiffness (mm Hg/ml) 0.21 1.27 0.52 0.24 End-diastolic volume (ml) 73.81 153.77 114.27 20.26 Stroke volume (ml) 32.67 93.97 66.20 15.56 Ejection fraction 0.34 0.75 0.58 0.11 LVOTAcc (cm/s2) 4.01 28.50 16.59 7.94

Ave = average; EDP = end-diastolic pressure; LV = left ventricular; LVOT_Acc = left ventricular outflow tract systolic acceleration.

	Footnotes

 
Supported, in part, by a grant of the Fédération Francaise de Cardiologie, Paris, France and grant NCC9-60 and NCC9-58, National Aeronautics and Space Administration, Houston, Texas.

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