Aortic Function in Arterial Hypertension Determined by Pressure-Diameter Relation
Effects of Diltiazem
Background Aortic elastic properties, important determinants of left ventricular function and coronary blood flow, are compromised in hypertension. The aim of this study was to determine aortic function in hypertensive patients and in normal subjects before and after administration of diltiazem, a calcium antagonist widely used in the treatment of essential hypertension.
Methods and Results The aortic pressure-diameter relation was obtained before and after diltiazem administration in 15 hypertensives and 15 control normotensives. Instantaneous diameter of the thoracic aorta was acquired with a high-fidelity intravascular catheter developed in our institution and previously validated. Instantaneous aortic pressure was measured simultaneously and at the same aortic level with a catheter-tip micromanometer. Energy loss due to the viscosity of aortic wall was measured from the area of the loop. Aortic distensibility was calculated using the formula 2×(pulsatile change in aortic diameter)/([diastolic aortic diameter]×[aortic pulse pressure]). At baseline, aortic distensibility was lower and energy loss was greater in hypertensives than in normotensives (distensibility: 1.4±0.3 versus 3.5±0.7 cm2 · dyne−1 · 10−6, respectively, P<.001; energy loss: 14.1±3.3 versus 8.2±2.2 mm · mm Hg, respectively, P<.001). After diltiazem administration, aortic distensibility was increased, whereas energy loss was decreased in both hypertensives (peak response: distensibility, 2.0±0.4 cm2 · dyne−1 · 10−6, P<.001; energy loss, 9.3±1.6 mm · mm Hg, P<.001) and normotensives (peak response: distensibility, 5.2±0.5 cm2 · dyne−1 · 10−6, P<.001; energy loss, 5.0±1.2 mm · mm Hg, P<.001).
Conclusions Aortic elastic properties are compromised and energy loss due to aortic wall viscosity is increased in hypertensives compared with normotensives. Function of the aorta is improved in both hypertensive and normotensive subjects after the administration of diltiazem.
Aorta functions not only as a conduit delivering blood to the tissues but also as an important modulator of the entire cardiovascular system, buffering the intermittent pulsatile output from the heart to provide steady flow to capillary beds.1 By virtue of its elastic properties, aorta influences left ventricular function and coronary blood flow.2 3 4 5
Systemic hypertension, a common disorder with potentially serious complications, exerts further ill effects through structural and functional modifications of the arterial wall.6 7 Previous studies using different techniques have shown that aortic elastic properties are compromised in patients with arterial hypertension.8 9 10 11 12 13 14 Measurement of pulse wave velocity has been extensively used,9 10 11 providing only indirect estimations of the elastic properties of the aorta. Noninvasive methods11 12 13 14 using formulas involving pulsatile change in aortic dimensions and pulse pressure (the former is measured with echocardiography or nuclear magnetic resonance and the latter is measured with conventional sphygmomanometer or noninvasive pressure recorders) determine the elastic properties of the aorta at a given level; however, they do not provide insights into the mechanism, whether active or passive, involved in the alterations of the elastic properties of the aorta. Such information is provided with aortic pressure-diameter relation. Recently, we described a new method to obtain aortic pressure-diameter relation in conscious humans.15 16 17 With this method, aortic diameters were acquired with a high-fidelity intravascular catheter developed in our institution that incorporates an ultrasonic displacement meter at its distal end. Aortic pressures were acquired simultaneously and at the same aortic level with a catheter-tip micromanometer.
Previous studies by us18 and others19 have shown that nifedipine administration increases the distensibility of the aorta. Moreover, studies in experimental animals have shown that diltiazem improves aortic elastic properties.20 The purpose of the present study was to investigate the effect of diltiazem, a calcium channel antagonist widely used in the treatment of arterial hypertension, on aortic performance in hypertensive and normotensive subjects using a high-fidelity method for the determination of pressure-diameter relation.
All patients with an age range from 30 to 70 years who underwent diagnostic cardiac catheterization for evaluation of chest pain and were shown to have angiographically normal coronary arteries were considered eligible for inclusion in the study. Patients were excluded if they had significant valvular heart disease, congenital heart disease, hypertrophic cardiomyopathy, left ventricular ejection fraction of <55%, chronic obstructive pulmonary disease, congestive heart failure, diabetes mellitus, or any other systemic disease. All patients discontinued medications, if any, for at least five half-lives before the study. Thereafter, patients with a history of hypertension were examined and qualified for inclusion in the hypertensive group if sitting auscultatory diastolic blood pressure at repeated measurements was 95 to 114 mm Hg at rest without medication (moderate hypertension). Essential uncomplicated hypertension was confirmed by standardized explorations performed during 1-day hospitalization. Finally, 15 hypertensives fulfilling the above criteria were selected. Moreover, 15 age- and sex-matched subjects without a history of arterial hypertension and blood pressure consistently of <140 mm Hg systolic and <90 mm Hg diastolic were selected and included in the normotensive group. Subjects’ standard biology was normal. Moreover, total cholesterol, HDL cholesterol, and triglycerides levels did not differ between the two groups. The protocol was approved by our institutional ethics committee, and all patients gave informed consent before participation.
Measurement of Aortic Diameter and Pressure
Instantaneous aortic diameters and pressures were recorded simultaneously and at the same point of the aorta. This technique has been recently described in detail.15 16 17 Diameter was measured in the proximal descending aorta with a Y-shaped intravascular catheter that was developed in our institution and involves the use of sonometry for the measurement of diameters. At each arm of the catheter, a piezoelectric crystal (5 MHz in frequency, 1 mm; Crystal Biotech) is attached. The technical characteristics of the device include (1) resolution for assessment of changes in diameter of 10 μm, (2) flat (±5%) frequency response in testing up to 40 Hz, (3) no measurable phase lag between forced oscillations of the device and the signal in the frequency response range, and (4) minimal loading on the aortic wall (0.45 g/arm when the distance between the arms is 1 cm).
Aortic pressures were recorded with a catheter-tip micromanometer (model SPC-330; Millar Instruments). The transducer was calibrated electronically against mercury at the beginning of each study.
The subjects were studied during a 1-day hospitalization. Studies were performed at 9 am under a controlled room temperature of 20±1°C. For patients in the hypertensive group, study of aortic function was performed on a separate catheterization session within 6 months after the diagnostic catheterization. For patients in the normotensive group, diagnostic cardiac catheterization and study of aortic function were performed in the same catheterization session. Before insertion of the diameter device and pressure micromanometer, all patients received an intravenous bolus injection of heparin (100 U/kg), and during the procedure, continuous infusion of heparin was administered to maintain activated clotting time of >300 seconds.
For insertion of the diameter device, a long (50-cm) 8F guiding sheath was introduced through a 9F introducer placed in the right femoral artery and positioned to the level of the proximal descending aorta under fluoroscopic observation. The catheter (with the wires collapsed) was then advanced into the guiding sheath. Once the catheter tip was in position, the guiding sheath was withdrawn to completely expose the Y-shaped end of the catheter, which allowed the arms to spread apart until they touched the aortic wall and freely followed its movements during the cardiac cycle. The catheter position was frequently checked by fluoroscopy throughout the study to document its stability.
The catheter-tip micromanometer (3F) was inserted through a 5F introductory sheath punctured into the left femoral artery and advanced minimally below the exact level of the pair of crystals.
Baseline measurements were obtained 30 minutes after the last infusion of contrast medium. After baseline measurements, diltiazem was administered intravenously through a peripheral line in a bolus dose of 0.15 mg/kg over a period of 2 minutes. Hemodynamic and ECG measurements were continuously monitored and recorded at baseline, at the end of diltiazem administration (time 0), and repeatedly thereafter (minutes 1 through 10, 15, and 20).
Throughout the study, ECG, aortic diameter, and aortic pressure signals collected with a VF-1 mainframe fitted with appropriate modules for acquisition of data were simultaneously displayed in real-time mode on a PC (Pentium 100) using a multichannel 12-bit analog-to-digital converter (Data Translation Inc) and commercially available data acquisition software (Dataflow; Crystal Biotech). The digitized data were stored and later processed with the use of commercially available software (Microsoft Excel for Windows). Signals were digitized every 5 msec. For aortic pressure and diameter values and subsequent calculations of derivative parameters, analyses were performed on 10 consecutive cycles, and the results were averaged.
Indexes of Aortic Elastic Properties
Aortic strain was calculated as the following ratio: Aortic Strain=(Systolic−Diastolic Aortic Diameter)/Diastolic Aortic Diameter.
Aortic pressure-diameter relation15 16 17 was obtained by plotting the pressure versus diameter of digitized data with commercially available computer software (Excel for Windows; Fig 1⇓). To characterize the pressure-diameter relation and determine the aortic loop orientation, the slope and intercept of the linear regression line of pressure versus diameter were calculated. Moreover, aortic pressure-diameter data obtained during the ventricular ejection, which corresponds to the ascending limb of the loop, were used for the calculation of aortic stiffness constant. The rate of aortic blood pressure changes (dP/dt) was instantaneously calculated and simultaneously recorded with the high-fidelity pressure. Pressure and diameter data during the ascending limb of the loop, starting when the dP/dt curve reached zero baseline (at the beginning of ascending limb of the loop) and ending at peak +dP/dt, were fitted to the exponential function: P=b×ea ·D, where P is the instantaneous aortic pressure and D is the aortic diameter. The least-squares method was used for calculation of a and b, where a is the elastic aortic stiffness constant (mm−1), which determines the slope of the exponential curve, and b is the elastic constant (mm Hg; Fig 2⇓).
Aortic energy loss due to the viscosity of the aortic wall was represented by the area (mm · mm Hg) within the aortic loop.
Wave reflections were evaluated by measuring augmentation index2 24 defined as the ratio of (Pressure From Inflection Point to Late Systolic Peak)/(Pulse Pressure). Beginning of pressure wave upstroke, inflection point (Pi), and late systolic peak (Ppk) were defined by using fourth derivative of pressure.24
Data are presented as mean±SD. For comparisons of patient characteristics between the two groups, the unpaired t test was used. Changes during the study within each group were evaluated using ANOVA. Values of peak response to diltiazem administration were compared with baseline using the paired t test. Qualitative data were compared with use of the χ2 test. Correlations were evaluated with the Pearson’s coefficient of correlation. A value of P<.05 was considered statistically significant.
Demographic and Baseline Characteristics
Subjects’ characteristics and comparisons between groups at baseline are presented in Table 1⇓. Age, sex ratio, body surface area, and cardiovascular risk factors were similar in the two groups.
Aortic Pressures and Diameters
Systolic, diastolic, and pulse pressures were significantly higher in the hypertensive group. End-systolic aortic diameter did not differ, whereas end-diastolic diameter was greater and strain was lower in hypertensives.
Distensibility was lower in the hypertensive subjects. The clockwise pressure-diameter loops of hypertensive patients were shifted upward and rightward, and they had a steeper slope, as well as a lower intercept indicating reduced elasticity compared with controls (Fig 1⇑). The pressure-diameter data fitted excellently to the monoexponential function P=b×ea · D, (r=.97 to .99, P<.001), and the aortic stiffness constant a was higher in hypertensives than in normotensives. Moreover, energy loss was greater in hypertensives than in normotensives.
Augmentation index was significantly lower in the normotensive group.
Response to Diltiazem Administration
Diltiazem administration did not significantly change the heart rate in both groups. Peak response to diltiazem administration concerning all measured parameters, as well as calculated aortic function indexes and augmentation index, occurred during the first minute after drug infusion completion in both groups (Table 2⇓ and Fig 3⇓).
Aortic Pressures and Diameters
Systolic and diastolic aortic pressures were decreased in both hypertensives and controls (baseline versus peak, P<.001; ANOVA, P<.001 for all, Fig 3⇑). Moreover, pulse pressure decreased both in hypertensives (baseline versus peak, P<.001; ANOVA, P=NS) and normotensives (baseline versus peak, P<.005; ANOVA, P=NS). Diameters remained unchanged in the hypertensive group, whereas systolic diameter increased (baseline versus peak, P<.001; ANOVA, P<.05) and diastolic diameter decreased (baseline versus peak, P<.05; ANOVA, P=NS) in the normotensive group.
Aortic strain increased both in hypertensives (baseline versus peak, P<.001; ANOVA, P<.005) and normotensives (baseline versus peak, P<.001; ANOVA, P<.001).
Diltiazem administration resulted in an improvement of pressure-diameter relation–derived elasticity indexes that was associated with a downward and rightward shift of the pressure-diameter loops of both hypertensive patients and controls (Fig 2⇑). Distensibility increased significantly in both groups (baseline versus peak, P<.001; ANOVA, P<.001 for both, Fig 3⇑). Slope of the loop became less steep in both hypertensives (baseline versus peak, P<.001; ANOVA, P<.005) and normotensives (baseline versus peak, P<.001; ANOVA, P<.01), stiffness constant decreased in both hypertensives (baseline versus peak, P<.001; ANOVA, P<.005, Fig 3⇑) and normotensives (baseline versus peak, P<.005; ANOVA, P=NS, Fig 3⇑), and intercept increased in both hypertensives (baseline versus peak, P<.001; ANOVA, P<.001) and normotensives (baseline versus peak, P<.001; ANOVA, P<.01). Shifting of the pressure-diameter loops to another hypothetical line of elasticity (see “Discussion”) represents an active mechanism of aortic elastic properties improvement.15 16 17 The energy loss (area of loop) was significantly reduced in both groups (baseline versus peak, P<.001; ANOVA, P<.001 for both).
Augmentation index decreased significantly in both hypertensives (baseline versus peak, P<.005; ANOVA, P=NS) and normotensives (baseline versus peak, P<.001; ANOVA, P<.05) indicating reduced wave reflection in the periphery.
Correlation Between Aortic Distensibility and Aortic Stiffness Constant
A very good inverse correlation (Fig 4⇓) was found between distensibility and aortic stiffness constant in normal subjects and hypertensives both before (r=−.77 and r=−.86, respectively; P<.001 for both groups) and after (r=−.66 and r=−.70, respectively; P<.01 for both groups) diltiazem administration. An excellent inverse correlation was also found between distensibility and aortic stiffness constant when data from all patients, before and after diltiazem, were plotted altogether (r=−.96, P<.001).
To the best of our knowledge, the present study is the first to demonstrate the behavior of the pressure-diameter relation in hypertensive and normotensive subjects both before and after the administration of a calcium antagonist, diltiazem, using a high-fidelity method. According to our findings, aortic stiffness and energy loss due to wall viscosity are increased in hypertensives compared with normotensives. Moreover, diltiazem administration produced an acute improvement of aortic elastic properties and a reduction of viscous energy loss in both groups.
The method used in the present study provides an accurate determination of pressure-diameter relation. The high-fidelity diameter-measuring device has been validated in experimental and clinical studies and proved to be accurate and safe for the measurement of aortic diameter.15 16 Aortic pressure was measured by a catheter-tip micromanometer, which allows excellent reproduction of pressure waveforms. Moreover, aortic pressure was measured simultaneously with aortic diameter and, at the same point, two features mandatory for the reliable determination of pressure-diameter relation.15
Analysis of the pressure-diameter loop provides a valuable insight into aortic mechanics. First, indexes such as distensibility and slope of the pressure-diameter loop may be calculated. Moreover, in the present study, aortic stiffness constant was measured from pressure and diameter data of the aortic filling phase through the use of a simple monoexponential curve fit with high correlation coefficients, and, as was demonstrated, this index of aortic elasticity correlates well with established indexes such as aortic distensibility. Second, study of the pressure-diameter relation helps distinguish between active and passive changes in aortic elastic properties. The pressure-diameter relation for a given subject has a sigmoid configuration. Movement of the pressure-diameter loop along this hypothetical sigmoid line suggests changes of the elastic properties of the aorta due to changes in aortic pressure alone. In contrast, shifting of the pressure diameter loop to the right or left implies essential modification of the intrinsic elastic properties of the aorta due to nonpassive factors.15 16 17 Third, study of the pressure-diameter loop provides insights into aortic energetics. In specific, the area within the loop represents the energy dissipated due to the viscosity of the aortic wall.
Aortic Function in Hypertensive Patients
The results of the present study confirmed that aortic elastic properties are compromised in essential hypertension.8 9 10 11 12 13 14 Several studies25 26 27 suggested that in hypertension, the aorta exposed to increased intraluminal pressure undergoes an increase in mural thickness. Moreover, changes in the structural components of the arterial wall, including a fall in the ratio of elastin to collagen, may account for stiffening of the aorta.28 In addition, increased smooth muscle tension is possible contributor to aortic wall stiffening in hypertension. Hypertension-induced endothelial cell dysfunction may also contribute to alterations of the arterial wall tone, most likely through impairment of nitric oxide–mediated vascular smooth muscle relaxation.29 In advanced stages of the disease, a further factor that reduces arterial compliance is deposition of calcium.30
Response to Diltiazem Administration
We demonstrated that aortic function is improved after the administration of diltiazem to both hypertensives and normotensives. This finding is in accordance with previous observations in experimental animals.20 Two mechanisms may be involved in these changes. First, the improvement in aortic elasticity might be considered a passive phenomenon due to the lowering of the aortic pressure. Second, an active mechanism may contribute in the changes observed. Indeed, the pressure-diameter loop was shifted downward after diltiazem administration along a different hypothetical sigmoid line of elasticity. This movement suggests active changes of the elastic properties of the aorta (changes of the intrinsic elastic properties). Such an active effect of diltiazem could be due to a direct relaxation of the smooth muscle of the aorta.7 31 32 Moreover, because reduced vasa vasorum flow unfavorably affects aortic elastic properties,33 34 an increase in the vasodilatory capacity of the vasa vasorum of the aortic wall, which is decreased in chronic hypertension,35 may account for the active improvement in aortic elastic properties with the drug. Hypothetically, endothelial damage could perpetuate or even initiate hypertension. The proposed specific role of the vascular endothelium in producing vasoconstrictory endothelin and vasodilatory nitric oxide and the delineation of the endothelial site of action of calcium antagonists lead to the concept that these agents could interrupt a hypertensive vicious-cycle mechanism. Moreover, viscous energy loss was reduced in both groups, a factor that also implies modification of the intrinsic elastic properties of the aortic wall.
As indicated by the reduction in the augmentation index, diltiazem resulted in a decrease in peripheral resistance. Thus, this additional site of action may contribute to a beneficial effect of the drug on left ventricular afterload.
The possible effect of constant contact by the arms on smooth muscle tone was previously investigated.15 It has been proved that there is no smooth muscle response to the prolonged contact of the aortic wall by the arms of the device.
A limiting factor of the technique is its invasive nature. However, our method is best suited to physiological investigations in which detection of subtle changes of the elastic properties of the aorta are sought or reliable determination of the aortic pressure-diameter relation is desired. Furthermore, in neither this study nor previous studies15 16 17 were any complications encountered, thus confirming the safety of the technique.
Aortic distensibility is affected in the presence of cardiovascular risk factors.6 7 However, in our study population, the two groups had the same distribution of age, smoking, or cholesterol levels, thus overcoming a possible confusing effect of these factors on aortic elastic properties and their modification with diltiazem.
The results of the present study confirmed that elastic properties of the aorta are deteriorated in hypertensive patients compared with normotensive subjects and demonstrated that energy loss due to aortic wall viscosity was increased in the first group. Moreover, it was shown that diltiazem administration produces an acute improvement in the elastic properties of the aorta and a decrease in aortic energy loss in both groups. These effects may contribute the beneficial effects of diltiazem in the treatment of arterial hypertension.
This research protocol was supported by a grant from the Hellenic Heart Foundation.
- Received November 12, 1996.
- Revision received April 23, 1997.
- Accepted May 1, 1997.
- Copyright © 1997 by American Heart Association
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