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(Circulation. 1995;92:2210-2219.)
© 1995 American Heart Association, Inc.

Articles

Pressure-Diameter Relation of the Human Aorta

A New Method of Determination by the Application of a Special Ultrasonic Dimension Catheter

Christodoulos Stefanadis, MD; Costas Stratos, MD; Charalambos Vlachopoulos, MD; Stelios Marakas, MD; Harisios Boudoulas, MD; Ioannis Kallikazaros, MD; Eleftherios Tsiamis, MD; Konstantinos Toutouzas, MD; Lambros Sioros, MD; Pavlos Toutouzas, MD

From Hippokration Hospital (C. Stefanadis, C. Stratos, C.V., S.M., I.K., E.T., K.T., L.S., P.T.), Department of Cardiology, University of Athens, Greece; and Department of Cardiology (H.B.), Ohio State University, Columbus.

Correspondence to Christodoulos Stefanadis, MD, 9 Tepeleniou St, Paleo Psychico, Athens 154 52, Greece.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background Pressure-diameter relation of the aorta provides important information about the elastic properties of the vessel. However, owing to methodological limitations, data regarding this relation are limited in conscious humans. In the present study, we assessed a new method for the direct estimation of the elastic properties of the aorta in conscious humans by simultaneous acquisition of instantaneous aortic pressure and diameter.

Methods and Results With this method, instantaneous diameter of the thoracic aorta was acquired by a newly designed intravascular catheter developed in our institution that incorporates an ultrasonic displacement meter at its distal end. Instantaneous aortic pressure was acquired simultaneously at the same aortic level with a catheter-tip micromanometer. Aortic pressure-diameter loops were derived from computer analysis of data. After in vitro and animal testing, elastic properties of the aorta were investigated in coronary artery disease (CAD) patients (n=15) and compared with those of control subjects (n=10). Aortic distensibility was less in the CAD group than in the control group (1.73±0.33 versus 3.95±1.09x10^-6xcm²xdyne^-1, P<.001). Compared with control subjects, the mean value of the slope of the pressure-diameter loops was significantly greater in the CAD group (38.89±8.75 versus 19.62±5.46 mm Hg · mm^-1, P<.001), whereas the mean value of the intercept was lower in this latter group of patients (-785.60±177.55 versus -313.43±126.41 mm Hg, P<.001). An excellent correlation was found between the slope of pressure-diameter loop and age in the group of control subjects (r=.827). Ninety-three percent of the patients with CAD had values above the upper 95% confidence limits of the control subjects (P<.001). In a third group of patients (n=16) in whom assessment of pulse wave velocity was also included in the study of the elastic properties of the aorta, pulse wave velocity had a strong inverse correlation with aortic distensibility (r=-.95) and a strong positive correlation with the slope of the pressure-diameter loop (r=.97).

Conclusions This new method of determination of pressure-diameter of the aorta enables an accurate and reliable evaluation of the elastic properties of the aorta in conscious humans and may be useful for a profound study of human aorta mechanics.

Key Words: elasticity • pressure • aorta • waves • catheters

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
It is well appreciated that the aorta is not a simple conduit for the distribution of blood but rather has a fundamental role in the function of the cardiovascular system. Because of the physiological importance of the aorta, extensive experimental testing under in vitro and in vivo conditions has been applied to determine its elastic properties.^{1 2 3 4 5 6 7 8 9 10 11 12 13} In humans, noninvasively acquired pulse wave velocity has been used to estimate the elastic properties of the aorta.¹⁴ However, this index provides an overall estimation of the elastic properties of the entire aortic segment where pulse wave velocity is measured and does not represent the regional elastic properties at a given aortic level. Regional elastic properties of the human aorta have been estimated in vivo with mechanical strain gauges,¹⁵ angiography,^{16 17 18} echocardiography,^{18 19 20 21 22 23 24} and magnetic resonance imaging techniques.^{25 26} However, elasticity indexes obtained with these methods provide insight into neither the distinction between passive and active effects on the elasticity of the vessel nor its viscoelastic properties in conscious humans. Information of this nature can be obtained with the study of pressure-diameter relation of the aorta in conscious humans. For the determination of this relation, instantaneous pressure and diameter should be obtained simultaneously and at the same aortic level. At present, however, data regarding aortic pressure-diameter relation in conscious humans are limited.^{27 28}

The feasibility of a new method for the direct estimation of the elastic properties of the aorta in conscious humans with simultaneous acquisition of instantaneous aortic pressure and diameter was assessed in the present study. With this method, aortic diameters were acquired with a newly designed intravascular catheter developed in our institution that incorporates an ultrasonic displacement meter. Aortic pressures were acquired at the same aortic level with a catheter-tip micromanometer. By this method, elastic properties of the aorta were investigated in patients with coronary artery disease (CAD) and compared with those of control subjects.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Measurement of Aortic Diameters and Pressures
Aortic diameters
The diameter-measuring instrument that was developed in our laboratory consists of a Y-shaped catheter. The body and each arm of the catheter consist of a 0.014-in stainless steel wire. At each tip of the catheter, a piezoelectric crystal (5 MHz frequency, 1 mm, Crystal Biotech) is attached (Figs 1 and 2). A polyurethane protective smooth-tip sheath covers the arms, the crystals and their lead wires, and the body of the catheter. The crystals oppose each other at any angle of the arms, which are spring-loaded and always tend toward the open position. The length of the arms is 7 cm, and the angle is 40° at the expanded configuration. The lead wires from the crystals end in a connector at the proximal part of the catheter (Fig 1).

View larger version (80K): [in this window] [in a new window]   Figure 1. Photograph of the device used to measure aortic diameter. Arrows indicate the distal tips of the Y-shaped catheter. Large arrowhead indicates the connector at the proximal end.

View larger version (113K): [in this window] [in a new window]   Figure 2. Photographs illustrating insertion of the diameter catheter into a glass model of the aorta. First, an 8F guiding sheath (S) is advanced to the desired level; then, the diameter catheter is advanced through the guiding sheath. When the catheter in position, the sheath is retracted gradually (A) to expose completely the tips of the catheter; the arms spread apart and touch the wall (B). Arrowheads indicate the 1-mm crystals inside the protective polyurethane sheath.

The principle of the ultrasonic dimension technique has been described previously.⁷ In brief, the transit time of acoustic impulses, traveling at the sonic velocity of approximately 1.5x10⁶ mm/s from the transmitting piezoelectric crystal to the opposing receiver crystal, is measured. A voltage proportional to transit time, and thus instantaneous dimension, is continuously recorded. Crystal alignment is verified after fabrication of the catheter with an oscilloscope (model 2120, B&K Precision) displaying the received ultrasonic signal. Similarly, continuous verification is obtained during the procedure.

The technical characteristics of the device were determined with the following performance tests.

The resolution for assessment of changes in diameter of the 5-MHz ultrasonic dimension crystals used in the present study is 10 µ, as determined by the manufacturer.

Frequency response testing of the diameter device up to 40 Hz showed a flat response.

There was no measurable phase lag between forced oscillations of the device and the signal in the frequency response range.

For evaluation of the possible mechanical impedance that the device exerts on the aorta, we measured the force that is exerted on the aortic wall by the catheter-tip arms. This force depends on the angle of the arms of the Y-shaped end of the catheter. For the model that was used in the present study, which is suitable for study of large vessels such as the aorta, the maximum force exerted is 0.45 g per arm when the distance between the arms is 1 cm. This value is less than those reported to be acceptable for the study of aortic mechanics,²⁹ and it is thus concluded that the device does not offer significant mechanical impedance to the motions of the aorta.

Aortic pressures
Aortic pressures are simultaneously obtained with a catheter-tip micromanometer (model SPC-330, Millar Instruments). This high-frequency response pressure gauge allows excellent reproduction of pressure waveforms and avoids time delay and motion artifacts associated with fluid-filled pressure catheters.

Procedure
For insertion of the diameter device, a long (50 cm) 8F guiding sheath was inserted through a 9F introducer placed through a puncture in the right femoral artery and advanced to the level of the proximal descending aorta. Then, the catheter-tip (with the wires collapsed) is inserted into the guiding sheath and advanced to the descending aorta. Once the catheter-tip is in position, the guiding sheath is withdrawn to expose completely the Y-shaped end of the catheter, which allows the arms to spread apart until they touch the aortic wall and follow freely its movements during the cardiac cycle (Fig 2). All of these manipulations for insertion and positioning of the catheter are performed under fluoroscopic observation.

The catheter-tip micromanometer (3F) is inserted through a 5F introductory sheath placed through a puncture into the left femoral artery. To permit recording of pressure and dimension at the same site, the catheter-tip micromanometer is advanced retrogradely under fluoroscopic control, and the tip is located minimally below the exact level of the pair of crystals to avoid distortion in the received ultrasonic signal by presenting an obstruction in the path of the propagated ultrasound.^{7 10} Fig 3 shows the tips of the Y-shaped catheter and the tip of the catheter-tip micromanometer within the thoracic descending aorta of a patient, on a fluoroscopic image (Fig 3A) and on an image obtained with transesophageal echocardiography (Fig 3B).

View larger version (87K): [in this window] [in a new window]   Figure 3. Radiographic (A) and echocardiographic (transesophageal; B) images of the diameter device and the pressure micromanometer positioned at the thoracic aorta. In the radiographic frame, large arrowheads indicate the crystals, and the small arrowhead indicates the tip of the catheter-tip micromanometer. In the echocardiographic image, white arrows indicate the crystals; the tip of the micromanometer is not imaged because it is located slightly below the level of the echo-band cross sectioning the thoracic aorta.

Data Acquisition and Processing
A VF-1 mainframe (Crystal Biotech) was fitted with appropriate modules for acquisition of aortic diameters, aortic pressures, and ECG. Ultrasonic crystals, pressure micromanometer, and ECG leads were connected to a 5-MHz length-gauge module (LG-510), a dual-pressure module (BP-1), and an ECG module, respectively. Signals of aortic pressure, aortic diameter, and ECG collected with VF-1 mainframe are simultaneously displayed in real-time mode on a personal computer (IBM 486 DX) with a multichannel 12-bit analog-to-digital converter (Data Translation Inc) and commercially available data acquisition software (Dataflow, Crystal Biotech). Signals are digitized every 5 ms. The sensitivity of the LG-510 length-gauge module, to which the crystals are connected, is 100 mV/mm.

The digitized data are stored and later processed with the use of commercially available software (Microsoft Excel for Windows).

For aortic pressure and diameter measurements and subsequent calculations, approximately 10 consecutive beats are averaged.

Fig 4 shows in a schematic view the dimension and pressure gauges positioned at the level of the proximal descending aorta.

View larger version (29K): [in this window] [in a new window]   Figure 4. Schematic representation of study instrumentation. Diameter device and catheter-tip micromanometer positioned at the thoracic aorta are connected to a mainframe (VF-1). Instantaneous diameter and pressure signals are displayed in real-time mode on the screen of a computer.

Experimental Testing
To test the feasibility, efficacy, and safety of the diameter-measuring device, the new method was applied in six experimental animals (pigs of either sex; weight, 15 to 23 kg). The animals were premedicated, anesthetized, and mechanically ventilated as previously described.¹³ The investigation conforms with the Guide for Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publication 85-23, revised 1985). Before insertion of the diameter device and the catheter-tip micromanometer, bolus heparin (100 U/kg) was administered; incremental heparin was administered during the procedure. The diameter and pressure gauges were inserted through surgically exposed iliac arteries and positioned in the descending thoracic aorta as described. Recordings were started when hemodynamic indexes (heart rate, aortic pressure, and aortic diameter) had reached a completely steady state after instrumentation.

The device-based method of measurement of aortic diameters was validated by comparison with the standard ultrasonic dimension-gauge method in three of the study pigs in the following manner. After baseline measurements were taken, the diameter device and the pressure micromanometer were removed. After midline laparotomy, the abdominal aorta was exposed, and a pair of free crystals identical to those used for fabrication of the device were implanted in the wall of the abdominal aorta with minimal dissection of the adventitia. Crystals were placed so that they opposed each other, and their lead wires were connected to the VF-1 mainframe for diameter measurements. Then, under fluoroscopic control, the diameter device was reinserted and positioned at a level just below that of the free crystals. When a completely steady state of hemodynamic indexes was reached, aortic diameter was measured with both the pair of free crystals and the diameter device.

On completion of measurements, the animals were killed while in deep anesthesia by administration of potassium chloride. The aorta was perfused in situ under constant pressure of 100 mm Hg with Ringer's lactate for 5 minutes and subsequently with Karnovsky's fixative fluid for 30 minutes. Transverse blocks of the thoracic aortic segments in which the catheter was placed were taken to include the entire circumference. Samples were placed in Karnovsky's fixative fluid, where they remained for 24 hours. The blocks of tissues were then cut longitudinally and separated into two parts. One half was further processed for light microscopy and the other half for scanning electron microscopy as previously described.^{13 30} The tissues for light microscopy were stained with hematoxylin and eosin and Masson's trichrome stains.

Clinical Study
One hundred twenty-seven consecutive male patients who underwent diagnostic cardiac catheterization for evaluation of chest pain were selected as potential subjects for the study. Patients with arterial hypertension (systolic arterial pressure 140 mm Hg and/or diastolic arterial pressure 90 mm Hg), valvular heart disease, history of previous myocardial infarction, congenital heart disease, dilated cardiomyopathy, left ventricular dysfunction, chronic obstructive pulmonary disease, history of cerebrovascular accident, or diabetes mellitus were excluded before entry into the study. With these criteria, 25 patients were selected and divided into two groups according to the angiographic result. Fifteen patients who had CAD (luminal stenosis 50% in diameter) in at least one of the major coronary arteries were included in the CAD group. Ten patients with angiographically normal coronary arteries were used as controls (patients with plaque disease, ie, patients with coronary atherosclerotic lesions causing luminal stenosis <50% in diameter, were also excluded). Treatment with all medications except aspirin was discontinued at least five half-lives before the study. All subjects had normal serum electrolytes, as well as normal renal and hepatic functions.

An additional 16 patients (4 women and 12 men; mean age, 45±15 years; age range, 25 to 75 years) who underwent diagnostic catheterization and did not necessarily meet the criteria were selected regardless of the angiographic result. In this third group of patients, pulse wave velocity was determined in addition to pressure-diameter relation studies.

Approval for the study was obtained from the institutional ethical committee, and written informed consent was obtained from each patient after each was provided with a detailed description of the protocol.

Diagnostic cardiac catheterization and studies of the elastic properties of the aorta were performed during the same catheterization session. Studies were performed in the morning after an overnight fast, without premedication, in a catheterization laboratory at a controlled room temperature of approximately 22°C. First, routine coronary arteriography and left ventriculography with nonionic contrast medium (Ultravist 370, Schering AG) were performed. Next, the 7F introducer in the right femoral artery was exchanged for a 9F introducer. In addition, a 5F introducer (except for studies of pulse wave velocity, where an 8F introducer was used for combined insertion of two pressure micromanometers) was inserted through a puncture in the left femoral artery. Before insertion of the diameter device and the pressure micromanometer, the patient received an intravenous bolus injection of 100 U/kg heparin and, during the procedure, continuous infusion of heparin to maintain activated clotting time of >300 seconds. Finally, the diameter device and the pressure micromanometer were inserted and advanced to the same level of the thoracic aorta (see "Procedure").

To allow patients to relax after diagnostic catheterization and instrumentation and thus to allow hemodynamic parameters to stabilize, as well as to exclude any effect of contrast medium on the elastic properties of the aorta, baseline measurements of all hemodynamic indexes were obtained approximately 20 minutes after instrumentation and at least 30 minutes after the last infusion of contrast medium.³¹

In the additional 16 patients in whom determination of pulse wave velocity was also included in the study of the elastic properties of the aorta, a second catheter-tip micromanometer inserted through the same 8F introducer was advanced to the thoracic aorta, and the pressure sensor was located 10 cm below the level of the dimension crystals. After baseline measurements for the determination of pressure-diameter relation, the first catheter-tip micromanometer positioned initially to the level of the dimension crystals was advanced, and its tip was positioned 10 cm above the level of the crystals, so that the distance between the two pressure sensors was 20 cm. Then, aortic pressures were recorded simultaneously with the use of the two micromanometers on photographic paper at a speed of 150 mm · sec^-1 with an Electronics for Medicine/Honeywell VR-12 device.

The possible alterations in smooth muscle cell tone that might be caused by the continuous contact of the arms of the catheter in prolonged studies was tested in the following manner. To produce a wide range of aortic pressures, three consecutive handgrip isometric tests (with a 30-minute interval between each exercise) were performed by four control subjects after the resting period that followed the instrumentation. To avoid variations in heart rate, exercises were performed during atrial pacing at a rate of 20 beats per minute above the individual baseline heart rate of each patient. A dynamometer was used for the isometric tests. The subjects were suitably instructed to avoid performing the Valsalva maneuver and carefully observed during the tests. During the 3-minute period of each consecutive isometric exercise at 50% of maximal voluntary contraction, aortic pressure and aortic diameter were recorded. Pulse-by-pulse values of peak systolic aortic pressures were plotted versus peak systolic diameters for each handgrip exercise. Likewise, pulse-by-pulse values of diastolic aortic pressures were plotted versus diastolic diameters (Fig 5A through 5C). Then, for each individual, the slopes and elevations of the three regression lines for both systolic and diastolic values were tested for significant differences (Fig 5D).³²

View larger version (15K): [in this window] [in a new window]   Figure 5. Effects of prolonged contact of the arms of the catheter device on aortic smooth muscle tone. A through C, Scatterplots of peak-to-peak values of diastolic (d) and systolic (s) pressures versus corresponding diastolic and systolic aortic diameter, at each of the three handgrip exercises of a single patient. Care was taken for all three plots to be performed for the same range of changes in peak systolic and diastolic pressures. D, Calculated regression lines of all three handgrip exercises. No significant difference was noted, indicating absence of alteration in aortic smooth muscle cell tone. rd and rs indicate Regression coefficients of the plotting of peak-to-peak values of both systolic and diastolic pressures versus corresponding diameters.

Determination of Pressure-Diameter Relation
Stored digitized data were processed with commercially available computer software (Excel for Windows). Aortic pressure-diameter relation was obtained by plotting the pressure (ordinate)- and diameter (abscissa)-digitized data.

Calculation of Aortic Distensibility
The distensibility of the aorta was calculated with the following formula^{11 13 15 16 17 18 21 33} :

where d is diastolic aortic diameter, d is systolic-diastolic aortic diameter (pulsatile change in aortic diameter), and P is systolic-diastolic aortic pressure (pulse pressure).

Determination of Pulse Wave Velocity
Theoretical pulse wave velocity was calculated from the following formula² :

where E_P is Peterson's pressure-strain elastic modulus, given by the following equation:

where g is gravitational constant and is blood density.

Measured pulse wave velocity was calculated as the ratio of the distance between the two pressure sensors to the delay time between the pressure waves recorded simultaneously with the two micromanometers as previously described.³⁴

Data and Statistical Analyses
Data values are expressed as mean±SD. All variables were tested for normal distribution with the Kolmogorov-Smirnov one-sample test. For comparison of patient characteristics between the two groups, the unpaired t test was used. Bivariate correlation coefficients were calculated with Pearson's product-moment method (continuous versus continuous variables) or with Spearman's rank method (continuous versus discrete variables) where appropriate. Linear regression analysis of pressure versus diameter was performed in each patient separately to determine the slope (ie, the regression coefficient b of the regression equation) and the intercept (ie, the a of the regression equation) of the regression line. These parameters, characterizing the pressure-diameter relation and the elastic properties of the aorta, were tested for differences between control subjects and CAD patients. The independent relations of the above slope of the pressure-diameter loop to its potential predictors were analyzed with stepwise multiple linear regression, both in the total study population (potential predictors: systolic pressure, diastolic pressure, age, diastolic diameter, presence or absence of CAD, and heart rate) and in the control subjects (potential predictors: systolic pressure, diastolic pressure, age, diastolic diameter, and heart rate). Moreover, to test for significant differences among the simple linear regression lines in the study for alterations in smooth muscle tone, an overall test for coincidental regressions was performed for the systolic and diastolic measurements separately.³² Linear regression analysis and the Bland-Altman method³⁵ were used to compare externally and internally measured aortic wall displacements for the validation of the diameter measurement technique. Nonlinear regression analysis was used to assess the relation between pulse wave velocity and aortic distensibility and between pulse wave velocity and slope of the pressure-diameter loop. A value of P<.05 was considered statistically significant.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Experimental Testing
In all experimental procedures, the diameter device could be inserted and positioned easily without difficulties or complications.

In gross inspection after each procedure, no thrombi were observed on the catheter. No embolic events were observed in any of the experimental pigs. Moreover, no thrombi were observed on the endothelial surface at the site of catheter placement.

Although not superimposable, the diameter tracings with the free crystals (external measurement) and the diameter device (internal measurement) were exactly similar, as shown in Fig 6A. There was an excellent correlation (r=1) between aortic wall displacements measured with the two pairs of crystals (Fig 6B). Moreover, there was a high degree of agreement between the external and internal aortic wall displacement (mean difference 0.0002 mm with a 95% confidence interval of -0.009 to 0.009 mm) with no obvious relation between the difference of the two methods for measuring wall displacement and their mean value (r=-.046; Fig 6C).

View larger version (44K): [in this window] [in a new window]   Figure 6. A, Tracings of aortic diameter measured by the free crystals (EXTERNAL) and by the diameter device (INTERNAL) in a single pig (the difference between external and internal aortic diameter represents 2xaortic wall thickness). Note that the tracings are identical. B, Plot showing excellent correlation between external and internal measurement of aortic wall displacement with data points clustering on the line of identity. C, Graph showing difference between external and internal measurements of aortic wall displacement versus their mean (mean difference 0.0002±0.0045 mm; P=NS; no relation between the difference and the mean, r=-.046). This figure demonstrates that there is a high degree of agreement between the two methods for measuring aortic wall displacement.

Scanning electron microscopy of the endothelial surface at the site of the catheter placement disclosed neither thrombus formation nor endothelial denudation. Light microscopy revealed no internal elastic lamina or deep wall damage.

Clinical Study
The diameter-measuring device could be inserted and positioned easily in all patients studied. There were neither technical difficulties nor complications. In all subjects, aortic pressure and diameter signals of excellent quality were obtained (Fig 7), and clockwise pressure-diameter loops were derived from analysis of data (Fig 8).

View larger version (12K): [in this window] [in a new window]   Figure 7. Simultaneous recordings of aortic pressure (A) and diameter (B) of a single cardiac cycle in a control subject (NL, patient A) and a patient with coronary artery disease (CAD, patient B). Note the reduced pulsatility in aortic diameter and the increased aortic diameter values in the patient with coronary artery disease compared with the control subject, despite the greater pulse pressure of the CAD patient.

View larger version (14K): [in this window] [in a new window]   Figure 8. Clockwise pressure-diameter loop of the same cardiac cycles of the patients in Fig 7. The loop of the coronary artery disease patient (CAD, patient B) has a steeper slope (P<.001), indicating reduced elasticity compared with control (NL, patient A).

The effect of handgrip exercise on aortic pressures and diameters is shown in Table 1. In each of the four patients, there were no significant differences among the three regression lines for both systolic and diastolic values of the consecutive handgrip tests (Fig 5D).

View this table: [in this window] [in a new window]   Table 1. Mean Values of Aortic Pressures, Diameters, and Distensibility at Baseline and With Handgrip Exercise

For CAD patients and control subjects, age, body surface area, and heart rate were similar (Table 2). Pulse pressure was greater in the CAD group (P<.05) than in the control group, whereas mean systolic and diastolic pressures were similar. Both mean systolic and diastolic aortic diameters were greater in the CAD group (P<.05 and P<.01, respectively), whereas mean pulsatile change in aortic diameter was greater in the control group (P<.001). Aortic distensibility was less in the CAD group compared with control subjects (P<.001, Table 2).

View this table: [in this window] [in a new window]   Table 2. Characteristics of Control Subjects and Patients With Coronary Artery Disease

Representative examples of pressure and diameter waveforms in a control subject and a patient with CAD are depicted in Fig 7, whereas respective pressure-diameter relations are shown in Fig 8. In Fig 7, a reduced aortic diameter pulsatility is observed in the CAD patient despite the increased pulse pressure, denoting lower distensibilty. The same association of CAD with aortic elastic properties is denoted by the steeper slope of the pressure-diameter loop (Fig 8).

Compared with control subjects, the mean value of the slope of the pressure-diameter loops was significantly greater in the CAD group (P<.001), whereas mean value of the intercept was lower in this latter group of patients (P<.001, Table 2). Both findings denote reduced elastic properties in the CAD patients.

In the group of control subjects, multiple regression analysis revealed that age was the only factor predictive of the slope of the pressure-diameter loop (F=17.267, R²=.683, P<.01), whereas in the total study population, CAD and age were found to be the most significant predictive factors (F=24.708, R²=.832, P<.001; Table 3). Therefore, to interpret the values of the slope of the pressure-diameter loop in patients with CAD, we constructed a nomogram of this slope to age. The 95% confidence limits of the derived regression line (slope of pressure-diameter loop versus age, r=.827) allowed a definition of statistical range for the values of the slope of control subjects. As shown in the scatterplot of Fig 9, 93% of the patients with CAD had values above the upper 95% confidence limits of the control subjects (P<.001).

View this table: [in this window] [in a new window]   Table 3. Multiple Regression Model Showing the Independent Linear Determinants of the Slope of the Pressure-Diameter Loop in the Coronary Artery Disease Patients and Control Subjects

View larger version (14K): [in this window] [in a new window]   Figure 9. Scatterplot of the slope of the pressure-diameter loops versus age in control subjects (NORMALS) and coronary artery disease patients (CAD). As depicted, 93% of the CAD patients had values above the upper 95% confidence limits of the control subjects.

There was no difference between the theoretical and the measured pulse wave velocity (7.7±3.5 versus 7.4±3.7 m/s, P=NS). Moreover, there was an excellent correlation between the theoretical and the measured pulse wave velocity (r=.98, P<.001). The measured pulse wave velocity had a strong inverse correlation with aortic distensibility (r=-.95, Fig 10A). In addition, this index was strongly correlated with the slope of the pressure-diameter linear regression line (r=.97, Fig 10B).

View larger version (10K): [in this window] [in a new window]   Figure 10. A, Relation of measured pulse wave velocity and aortic distensibility. B, Relation of measured pulse wave velocity and slope of the pressure-diameter linear regression line.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We assessed a new method for the direct estimation of the elastic properties of the aorta in conscious humans in the present study. The apparatus for the determination of the pressure-diameter relation consists of a newly developed transluminal catheter that uses an ultrasonic displacement meter for instantaneous diameter measurement and a catheter-tip micromanometer for simultaneous instantaneous pressure measurement.

Elastic Properties of the Aorta: Clinical Significance
Aortic elasticity is an important component of left ventricular afterload, constituting a major determinant of left ventricular power output.^{36 37} Moreover, aorta, by virtue of its viscoelastic properties, dampens the intermittently generated hydraulic energy of the left ventricle along the arterial tree and provides a continuous flow, which is fundamental for proper metabolic exchanges of tissues. In addition, aortic elasticity strongly influences coronary blood flow.^{12 25}

Determination of the Elastic Properties of the Aorta: Methodology
Several methods have been used for the evaluation of the regional elastic properties of the aorta in humans and involve determination of changes of aortic dimensions in relation to changes of aortic pressure.^{15 16 17 18 19 20 21 22 23 24 25 26} However, when changes in aortic pressure occur, it may be difficult to distinguish whether the changes of the aortic elasticity indexes used to estimate the elastic properties are secondary to changes of blood pressure, changes of the intrinsic elastic properties of the aorta, or both.

When the pressure-diameter relation is studied, changes of aortic elasticity related to pressure alone, within certain limits, can be defined. Changes of aortic elasticity due to changes in aortic pressure alone after an intervention will result in sliding of the aortic pressure-diameter loop upward or downward along the same hypothetical sigmoid curve of elasticity, whereas changes of the intrinsic elastic properties of the vessel will result in shifting of the loop either to the left or to the right. In addition, the rate of change of the aortic diameter during systole or diastole in health and disease states and after therapeutic interventions can be studied. Moreover, study of the pressure-diameter relation of the aorta provides insight into the viscoelasticity of the vessel. Pressure-diameter (or volume) relation of the aorta has been studied in experimental animals,^{1 2 3 5 6 8 9 10} whereas human data have been acquired postmortem³⁸ and during open heart surgery.¹⁵ Owing to methodological limitations, data regarding the study of pressure-diameter relation of the human aorta in conscious humans are limited.^{27 28} These limitations are mainly related to the fact that recordings must be instantaneous and simultaneous, leading in most of the cases to an invasive acquisition of pressure and diameter tracings. With most of the devices used until now, it has been difficult to avoid laparotomy or thoracotomy for measurement of the pressure-diameter relation of the aorta. However, it is of importance that anesthesia, thoracotomy, recent surgery, and acute manipulation of the vessel all modify responses of arterial smooth muscle to a variety of interventions,^{4 7 39} inducing a systematic error in the measurements and thus imposing the need for acquiring data in conscious humans. Another important factor for the reliable determination of the pressure-diameter relation is the simultaneous acquisition of data (pressure and diameter) at the same level of the aorta.

Imura et al²⁷ developed an apparatus for the determination of the elastic properties of the aorta that consists of an ultrasonic displacement meter for transcutaneous diameter measurement and a catheter-tip micromanometer for pressure measurement. Reported results are interesting; however, the limited approachability to all levels of the aorta with the ultrasonic displacement meter is an obvious limitation of the technique.

Recently, Lang et al²⁸ reported a method for the determination of regional elastic properties of the human aorta that involves the combination of transesophageal echocardiography with automated border detection and calibrated subclavian pulse tracings. The technique is very promising and may provide new insights into the physiopathology of disease states of the aorta. However, not all sites of the aorta are accessible with transesophageal echocardiography. Moreover, acquisition of aortic pressure at a different level than that of aortic diameter may affect the pressure-diameter relation.^{1 40} Finally, in the study of Lang et al, a remarkable percentage of patients was excluded owing to either inadequate detection of the aortic area or poor quality of the subclavian tracing.

Diameter-Measuring Device
Performance and experimental testing determined the accuracy of the diameter device, whereas experimental and clinical studies proved the feasibility, effectiveness, and safety of the apparatus for the determination of pressure-diameter relation. In addition, it was demonstrated that indexes of aortic elasticity measured with this apparatus correlate well with established indexes such as pulse wave velocity. With this method, estimation of the elastic properties of the aorta can be obtained in conscious humans during an ordinary heart catheterization, thus avoiding the influence of factors such as anesthesia, thoracotomy, acute manipulation of the aorta, and so on. The most important aspect of our method is that aortic diameters and pressures are measured simultaneously and accurately at the same point. When the distance between the pressure and diameter measuring points exceeds a certain limit, the hysteresis in the loop may be reduced or even abolished.¹ Besides, it has been reported that there is a change of pressure wave amplitude between central and peripheral arteries during drug studies, or when changes occur in heart rate or in relative content of ascending aorta pressure wave harmonics.⁴⁰ Therefore, although measuring diameter and pressure at different levels may not be a problem in screening studies, it is apparent that it may lead to errors when the detection of subtle changes is required. The diameter device is also characterized by high sensitivity, which is essential in measuring pulsatile diameter change in blood vessel because the change is very small. Moreover, the device can be used for estimation of the aortic elastic properties at different levels to obtain a "mapping" of the distensibility of the aorta.

Association of CAD and Age With the Elastic Properties of the Aorta
With the use of our new method, it was demonstrated that CAD is a potent independent factor associated with aortic elastic performance. This is in accordance with previous studies from our laboratory^{16 17 18 22} and other laboratories^{20 25 26} in which it was demonstrated that elasticity of the aorta is unfavorably affected in the presence of CAD. Deterioration of aortic elastic properties can be attributed to mechanical effect of atherosclerotic lesions and/or abnormal nutrition of the aortic wall.^{11 13 16 17 22}

Moreover, the results of the present study showed that age was an independent factor determining aortic elastic performance, both in control subjects and in the total study population. These findings are in agreement with previous studies showing that distensibility of the aorta decreases with age.^{14 26} Structural and macroscopic alterations of the aortic wall that are observed with advancing age^{34 41} may be responsible for the deterioration of the elastic performance of the vessel.

Specific Comments: Study Limitations
The possible effect of constant contact by the arms on smooth muscle tone in prolonged studies was studied during repeated handgrip exercises in the same individual. Our study indicates that there is no smooth muscle response to the prolonged contact of the aortic wall by the arms of the device.

A factor limiting the wide application of the technique is its invasive nature. However, this method is best suited to the detection of minute changes of the elastic properties of the aorta and not to the screening of patients, for which other noninvasive methods are more suitable.

Insertion of a relatively large introductory sheath into the femoral artery may lead to some to question the safety of the diameter-measuring device regarding arterial trauma. However, these sheaths are generally considered by interventional cardiologists to be safe. Also, in our total study population, no complications were encountered, thus confirming the safety of the diameter-measuring device. However, refinement of the device will allow for the use of smaller sheaths to minimize the risk of arterial damage.

Perspectives
More than 100 subjects were studied in several experimental protocols. The applicability of this device in the study of the elastic properties of the aorta appears to be wide. The dynamic elastic modulus may describe the elastic properties of the vessel; however, it contains no information about the viscous, or time-dependent, behavior of the vessel wall. Information of this nature is provided by estimation of the components of the complex modulus, which in turn can be obtained by analysis of instantaneous aortic pressures and diameters recorded simultaneously and at the same point.⁴² Thus, a more profound study of aortic elastic properties can be obtained by the newly developed apparatus in conditions in which elastic properties of the aorta have been found to be affected, such as advanced age^{14 23 26} or essential hypertension,^{21 23} as well as in many others in which these properties are expected to be altered, such as diabetes mellitus, diseases of the connective tissue, and so on. Moreover, the effect of several pharmacological agents can be studied, whereas insights can be gained into the potential mechanisms by which these drugs act. The high sensitivity of the device makes it ideal for the study of subtle changes in aortic elastic properties before the underlying disease becomes clinically evident. Moreover, further refinement of the diameter device will allow its application to smaller caliber vessels with a view to a more extensive study of the elastic properties of the arterial tree.

In conclusion, the newly developed diameter-measuring device enables an accurate and reliable determination of the elastic properties of the aorta in conscious humans and may serve as a useful means for a profound study of human aorta mechanics.

	Acknowledgments

 
This study was supported by a grant from the Hellenic Heart Foundation.

Received January 30, 1995; revision received April 18, 1995; accepted May 3, 1995.

	References

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