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Circulation. 1995;91:2669-2678

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(Circulation. 1995;91:2669-2678.)
© 1995 American Heart Association, Inc.

Articles

Effect of Vasa Vasorum Flow on Structure and Function of the Aorta in Experimental Animals

Christodoulos Stefanadis, MD; Charalambos Vlachopoulos, MD; Panagiotis Karayannacos, MD; Harisios Boudoulas, MD; Costas Stratos, MD; Theodoros Filippides, MD; Manolis Agapitos, MD; Pavlos Toutouzas, MD

From the Department of Cardiology, Hippokration Hospital, University of Athens, Greece, and the Department of Cardiology, Ohio State University, Columbus (H.B.).

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


*    Abstract
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 *Abstract
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down arrowResults
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Background It is known that vasa vasorum flow contributes substantially to the nutrition of the outer layers of the thoracic aorta. This investigation was undertaken to test the hypothesis that impairment of vasa vasorum flow would alter the structure of the aortic wall and change the elastic properties of the aorta.

Methods and Results The periaortic fat that contains the vasa vasorum for the ascending aorta was removed in seven anesthetized dogs, and the results were compared with those obtained from six weight-matched sham-operated control dogs. Aortic pressures, aortic diameters, and aortic distensibility were obtained before and 30 minutes and 15 days after removal of the periaortic vasa vasorum network. Aortic pressures were measured directly with a fluid-filled catheter. Aortic diameters were measured simultaneously with aortic pressures with an elastic, air-filled ring connected to a transducer. Aortic distensibility was calculated by the formula 2xpulsatile change in aortic diameter/(diastolic aortic diameterxpulse pressure). Histology was performed in transverse blocks of aortic wall at the end of the experiment in both groups. The efficacy of the technique for the interruption of vasa vasorum blood supply to the aortic wall was demonstrated by histology in four additional animals that were killed without removal of vasa vasorum (two animals) and immediately after vasa vasorum removal (two animals). At baseline, heart rate, aortic pressures, aortic diameters, and aortic distensibility were similar in the two groups. A significant decrease in aortic distensibility was observed 30 minutes and 15 days after removal of the vasa vasorum in the experimental group (baseline, 3.453±1.023; 30 minutes, 2.521±0.760; 15 days, 1.586±0.488 10-6 · cm2 · dyn-1; F=9.532, P<.001). No changes were observed in aortic distensibility in the control group during the experiment. Histology of the aorta revealed medial necrosis, alterations of the elastin fibers, and a trend (P=.055) for altered collagen-to-elastin ratio in a region occupying more than the one (outer) half of the media of the experimental group animals. No changes were observed in the control group.

Conclusions The findings of the present study demonstrated that interruption of vasa vasorum flow led to an acute decrease in the distensibility of the ascending aorta. Moreover, structural changes of the aortic wall and further deterioration of the elastic properties of the aorta occurred 15 days after vasa vasorum removal.


Key Words: aorta • elasticity • microcirculation • ischemia • structure


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
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It is known that vasa vasorum flow supplies the adventitia and most of the media of the thoracic aorta with nutrients. Vasa vasorum flow, therefore, may play an important role for aortic wall structure and function.1 2 3 4 5 6 7 8 9 10

Previous studies from our laboratory showed that aortic distensibility was decreased significantly 30 minutes after the removal of vasa vasorum in experimental animals compared with baseline.1 In the same study, preliminary observations suggested that medial necrosis may occur after vasa vasorum removal. The aim of the present study was to assess chronic changes in aortic distensibility after vasa vasorum removal and to determine a possible relation between these changes and structural abnormalities of the aortic wall. For this purpose, aortic distensibility was measured both 30 minutes and 15 days after vasa vasorum removal, and extensive histological studies of the aortic wall were performed.


*    Methods
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 *Methods
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Experimental Animals and Procedures
Seventeen healthy mongrel dogs of either sex, weighing between 13 and 21 kg, were studied. Of these, 13 were used for the study of aortic distensibility and structure and 4 for validation of the vasa vasorum removal technique.

The 13 animals in which aortic distensibility and structure were studied were premedicated with diazepam (0.25 mg/kg IV) and atropine (0.005 mg/kg IV). Anesthesia was initiated with sodium pentobarbital (30 mg/kg IV). To provide a steady anesthetic state, supplementary doses were given throughout the experiment. After intubation, the animals were connected to a volume respirator (Harvard) and were mechanically ventilated with room air. To obtain measurements, respiration was interrupted for short intervals.

A left thoracotomy was performed through the fourth intercostal space. The pericardium was opened longitudinally and the heart suspended in a pericardial cradle.

This investigation was approved by the review committee of our institution and was performed in accordance with the guiding principles of the American Physiological Society.

Aortic Pressure Measurements
A 4F fluid-filled catheter was advanced through the left subclavian artery to the ascending aorta under fluoroscopic control and connected through a pressure transducer (Statham P23Db) to a DR-8 recorder (Electronics for Medicine Inc).

Aortic Diameter Measurements
A special air-filled ring, manufactured in our research and development laboratory and sensitive in detecting changes of the aortic diameters, was placed around the aortic root 2 cm distal to the coronary arteries in each animal. This low-compliance device consisted of an elastic latex air-filled ring connected through a rigid tube to a transducer as described previously from our laboratory.1 Fluctuations in diameter of the aorta due to the pulsatile flow produced changes in the pressure of the air inside the ring and were recorded as a waveform. Rings of appropriate sizes were used to fit into the aortic root of each individual animal. The use of the air-filled ring was preferred in the present study because this device is capable of estimating global changes in aortic diameter rather than changes in the distance between two points of the aortic wall.11 12 13 14 15 16

Before each experiment, the system was calibrated against known increments of diameter as follows: The air-filled ring was placed around an elastic cylinder, the cylinder was subsequently filled with normal saline at a temperature of 37°C, and its diameter was increased gradually from 1.2 to 2.8 cm and correlated with the level of the signal recorded.1 Thus, from the waveform amplitude, the actual diameter of the cylinder could be measured.

The characteristics of the device have been described.1 In brief, they are as follows. Within the range of diameters encountered in this study, the calibration of the various devices used in the experiments was essentially linear, and the sensitivity ranged from 1.8 to 2.3 cm of recorder deflection per millimeter of diameter at maximum amplification. Frequency response of the system was found to be uniform (±5%) to 20 cycles per second. An essentially linear phase lag–versus–frequency relation of approximately 5° per cycle occurred through this frequency range.

Experimental testing regarding the mechanical impedance that the device might offer to the motions of the aorta showed that the device does not alter the stiffness of the aortic wall.1 Moreover, when measurements of diameters by the device were compared with high-resolution echocardiography in in vitro testing, there was no difference between the diameters obtained by the two methods, and an excellent correlation was found between them.1

Calculation of Aortic Distensibility
The distensibility of the ascending aorta was calculated from the formula: Aortic distensibility=2x{Delta}d/(dx{Delta}P), where d is diastolic aortic diameter, {Delta}d is systolic minus diastolic aortic diameter (pulsatile change in aortic diameter), and {Delta}P is systolic minus diastolic aortic pressure (pulse pressure).11 17

Experimental Protocol
The air-filled ring was initially placed around the ascending aorta through a small tunnel in the periaortic fat. Extreme care was taken to avoid, as far as possible, damage of the penetrating vasa vasorum.1 When the hemodynamic condition of the animal was considered stable, the filling pressure of the ring was adjusted to be 60 mm Hg at diastole; this filling pressure was in every case below the aortic diastolic pressure of the animal, so that the ring would be in gentle contact with the aortic wall. At systole, the filling pressure of the ring increased by approximately 5 mm Hg because of the distension of the aorta (the exact value depended on the amount of distension of the aorta). Conditions of contact between the ring and the aortic wall were stable throughout the experiment. After placement of the ring, changes of the aortic diameter were recorded simultaneously with the ECG and the aortic pressures at a paper speed of 50 mm/s. To evaluate the data of each experimental subject, 10 consecutive pressure and diameter complexes from the simultaneous recordings were measured and averaged.1

The 13 dogs in which aortic distensibility and structure were studied were then separated into two groups: Group A, the control group, consisted of 6 animals (weight, 17.6±2.8 kg); and group B, the experimental group, consisted of 7 animals (weight, 17.3±2.9 kg).

In group A, after the first recordings, the ring was removed and the animals remained in a stable anesthetic state; no further manipulations were performed on the ascending aorta. The ring was repositioned around the aorta 30 minutes later, and the same recordings were obtained.

In group B, after the first recordings, the ring was removed and all the perivascular fat containing the vasa vasorum network was carefully dissected and removed from the coronary arteries to the left subclavian artery. Bleeding was controlled with the application of gauzes moistened with normal saline at a temperature of 37°C. No diathermy was used.1 The ring was repositioned around the aorta 30 minutes later, and all recordings were repeated.

During the 30-minute interval from the first to the second recordings, dressings moistened with normal saline at a temperature of 37°C were applied on the ascending aorta of all animals of both groups. All manipulations were performed with extreme care to avoid damage of the aortic wall.

After the recordings, in all animals of both groups, the air-filled ring was removed, the pericardium and chest were closed, and the pneumothorax was treated. The catheter for the aortic pressures was then removed. All dogs recovered quickly from the operative procedure and were actively ambulatory and apparently in good health until they were killed.

Fifteen days after the initial procedure, all animals were premedicated, anesthetized, mechanically ventilated, and thoracotomized as described above. A 4F fluid-filled catheter was advanced through the left subclavian artery to the ascending aorta under fluoroscopic control, and the air-filled ring was again placed around the aorta. Recordings of aortic diameters and aortic pressures were obtained under conditions identical to those of the acute phase of the experiment.

After the final recordings, the animals were killed. In group A, transverse blocks of the wall of the ascending aorta, together with the adjacent periaortic fat, were cut to include the entire circumference. In group B, transverse blocks to include the entire circumference were cut from the region of the aortic wall supplied by the removed vasa vasorum; additional blocks were cut from a level beyond the area supplied by the removed vasa vasorum.

Validation of Vasa Vasorum Removal Technique
To test that the technique interrupted circulation to the aortic wall effectively, transverse blocks of aortic wall were cut from the area of interest to include the entire circumference in 4 animals. In 2 animals, the periaortic fat containing the vasa vasorum network was not removed. The animals were killed, and samples of the ascending aorta together with the intact adjacent periaortic fat were taken. The remaining 2 animals were anesthetized and operated on as for animals in group B and then killed after removal of periaortic fat containing the vasa vasorum network. Samples of the aortic wall and the removed periaortic fat were taken.

Histological Studies
All removed tissues were placed in formaldehyde 10% fixation fluid, where they remained for at least 24 hours. The blocks of tissues were then embedded in paraffin, sliced in 5-µm sections, and stained with hematoxylin-eosin, Verhoeff's elastica, Gomori, Masson's trichrome, and Sirius red (0.1% Sirius red F3BA dissolved in saturated picric acid, pH 2.0) stains. The sections were examined under a Zeiss light microscope.

Morphometric Studies
Medial thickness, considered to be the perpendicular distance between the innermost and the outermost medial elastic lamellae, was measured on microscopic sections by means of an eyepiece micrometer. Measurements were made at four positions, the first randomly chosen and the others at approximately 45°, 90°, and 135° around the vessel perimeter; the average of the four measurements was taken as medial thickness. The number of medial elastic lamellae at each of the measurement positions was counted; the average of the four counts was considered to be the total number of medial elastic lamellae.

Total elastin and collagen content was quantified by image analysis in the necrotic region in the experimental group and in the corresponding region in the control group by image analysis as previously described18 in appropriately stained (with Verhoeff's stain for elastin and with Sirius red stain for collagen) cross sections. The equipment included a video camera system fitted to the light microscope, a host computer (Olivetti PC 240), and an image analyzer (Optomax V, Analytical Measuring Systems Inc). Sections were studied with a x16 magnifying lens and projected onto a video camera as a monochromatic microscopic image at a final magnification with a calibration factor of 0.72 µm/pixel. In this monochromatic microscopic image, components of interest (elastin and collagen) were displayed in gray tones from dark gray to nearly black, whereas the other tissue components were displayed in gray tones from light gray to nearly white. By computer analysis, a 256-level gray-level histogram was obtained. In this histogram, the frequency of occurrence of pixels at each particular gray level was depicted at the ordinate and expressed as a percentage of the total area. By systematic scanning of a glass slide, a sequence of 30 nonoverlapping, randomly selected images from each area of interest was digitized. Subsequently, a composite histogram was obtained. The percentage of the area of the component of interest (elastin and collagen) for the particular histological section was obtained by calculating the integral of the part of this histogram above a certain threshold. This threshold was defined as the minimum of the gray-level histogram in histograms showing a bimodal distribution or as the change in slope of the distribution along its ascending portion for distributions without two clear modes.

Statistical Analysis
Values are expressed as mean±SD. For changes within each group regarding heart rate, aortic diameters, pressures, and distensibility, ANOVA for repeated measurements was used. In morphometric studies, comparisons between the two groups were performed with an unpaired t test.


*    Results
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*Results
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Baseline Characteristics
Body weight, heart rate, aortic pressures, aortic diameters, and aortic distensibility were similar in the two groups (Tables 1Down and 2Down).


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  		Table 1. Control Group: Body Weight and Hemodynamic Parameters at Baseline, 30 Min, and 15 Days After Initial Procedure


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  		Table 2. Vasa Vasorum Removal Group: Body Weight and Hemodynamic Parameters at Baseline, 30 Min, and 15 Days After Initial Procedure

Changes in Heart Rate, Aortic Diameters and Pressures, and Aortic Distensibility Within Each Group
In group A, the control group, there were no statistically significant changes in any of the measured parameters throughout the study period (Table 1Up, Fig 1ADown).



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  		Figure 1. Bar graphs showing aortic distensibility in the control group (A) and in the experimental group (B) at baseline and 30 minutes and 15 days after the initial procedure.

In group B, the experimental group (Table 2Up), heart rate, systolic aortic pressure, diastolic aortic pressure, and pulse pressure did not change significantly throughout the study period. A significant decrease in pulsatile change of the aortic diameter was observed in this group (F=11.364, P<.001). Compared with baseline, pulsatile change of the aortic diameter was lower both 30 minutes after vasa vasorum removal and 15 days after vasa vasorum removal (P=.05 and P<.001, respectively). Additionally, 15 days after vasa vasorum removal, pulsatile change in aortic diameter was significantly lower compared with 30 minutes after vasa vasorum removal (P<.05).

A significant decrease in aortic distensibility was observed in the experimental group (F=9.532, P<.001, Fig 1BUp). Compared with baseline, aortic distensibility was lower both 30 minutes and 15 days after vasa vasorum removal (P<.05 and P<.01, respectively). Additionally, aortic distensibility 15 days after vasa vasorum removal was significantly lower compared with 30 minutes after vasa vasorum removal (P<.05).

Histological Examination
The periaortic vasa vasorum network is shown in Fig 2ADown and 2BDown. In the animals that were killed immediately after vasa vasorum removal for validation of the technique for interruption of blood supply to the aortic wall, the vasa vasorum network was found to be removed completely. Neither hemorrhage nor trauma of the smooth muscle cells or the elastic lamellae was observed (Fig 2CDown).



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  		Figure 2. Histological studies (Gomori stain, x37.5). A and B, Cross sections of normal aorta showing the media (M) and the adjacent periaortic fat (F), which contains perivascular vasa vasorum network (arrowheads). C, Cross section of the aorta immediately after periaortic vasa vasorum network removal. Vasa vasorum have been completely removed. Asterisk indicates lumen.

In all the group A animals, all structures were apparently normal (Figs 3ADown and 4ADown).



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  		Figure 3. Cross sections of aortic wall at the end of the experiment (hematoxylin-eosin stain, x37.5). A, Aortic wall from an animal with intact vasa vasorum flow (vasa vasorum are indicated with arrowheads). Smooth muscle cells are evident throughout the whole thickness of the media. B, Aortic wall 15 days after vasa vasorum removal. In the inner part of the media (M) (zone 1), smooth muscle nuclei are evident, whereas in the outer part (zone 2), the media is devoid of nuclei, a finding consistent with ischemic necrosis. Zone 3 is transition zone. F indicates periaortic fat; asterisk, lumen.



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  		Figure 4. Cross sections of aortic wall at the end of the experiment (hematoxylin-eosin stain, x125). A, Media of an animal with intact vasa vasorum flow. Smooth muscle cells are apparently normal throughout the whole media. B, Transition zone (zone 3, see Fig 3BUp) of the media 15 days after vasa vasorum removal. Complete loss of smooth muscle cells is observed in the outer layers of the media, whereas smooth muscle cells appear normal in the inner layers. Top to bottom direction in each illustration indicates direction from outer to inner layers (Fig 3Up may be used as reference).

In all group B animals, necrosis (infarct) of the media had developed in the region that corresponded to the removed periaortic vasa vasorum network. At most levels, a uniform band of necrosis of the outer layers of the media more than one half its width completely encircled the entire circumference. In the necrotic zones, there was complete loss of smooth muscle cells. These zones bordered sharply on the viable inner medial layers (Figs 3BUp and 4BUp). In the necrotic zones, elastin fibers and their sheaths were preserved; however, they appeared uncoiled, dislodged, somewhat thinned, and focally fragmented (Figs 5Down and 6Down). In areas of both the necrotic and the viable zones located on both sides of the borderline of necrosis, close apposition of the elastic lamellae was observed.



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  		Figure 5. Cross section of aortic wall 15 days after vasa vasorum removal (Verhoeff's elastica stain; A and C, x125; B and D, x312.5). A and B, Inner viable layers (zone 1 of Fig 3BUp). Elastin fibers appear intact, retaining their normal sinuous pattern. C and D, Necrotic zone (zone 2 of Fig 3BUp). Elastin fibers are preserved, although they appear thinned, uncoiled, and spread apart. Asterisk indicates lumen.



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  		Figure 6. Cross section of aortic wall 15 days after vasa vasorum removal (Gomori stain; A and C, x125; B and D, x312.5). A and B, Inner viable layers (zone 1 of Fig 3BUp). Elastin fibers and their reticulin sheaths retain their normal appearance. C and D, Necrotic zone (zone 2 of Fig 3BUp). Elastin fibers and their reticulin sheaths are preserved, although uncoiled and spread apart. Asterisk indicates lumen.

In other sections bordering the central area of vasa vasorum removal, arclike areas with complete loss or reduced numbers of smooth muscle cells were found. In these sections, a close apposition of the elastic lamellae was frequently observed. In sections approximating the large vessels of the neck or the origin of the aorta, midzonal foci of the same necrotic lesions were also observed.

A proliferation of fibroblasts was observed in the adventitia, in which evidence of collagen formation was noted with Masson's trichrome and Sirius red stains. There was no leukocytic infiltration to the necrotic zone.

In the sections taken from the part of the aorta beyond the area of vasa vasorum removal, no alterations were observed, and all structures were apparently normal.

Morphometric Analysis
The thickness of the media was not different between the two groups at the time the animals were killed (group A, 1.39±0.33 versus group B, 1.44±0.31 mm, P=NS).

The total number of elastic lamellae did not differ between the two groups. Of interest, however, is the observation that although the inner viable zone of the media in the vasa vasorum removal group had a variable width depending on the total width of the media of the animal, the number of elastic lamellae in this zone was constant and equal to 28.4±2.6 elastic lamellae.

Collagen and Elastin Content
The percentage of collagen was not different in the two groups (group A, 22.15±1.96% versus group B, 20.59±2.48% of total area, P=NS, Fig 7Down). Elastin showed a trend, although it was not statistically significant, to be less in the experimental group compared with the control (42.77±6.15% versus 49.29±4.52% of total area, respectively, P=.055, Fig 5Up). Likewise, the collagen-to-elastin ratio showed a trend, although it was not statistically significant, to be higher in the experimental group compared with control (0.483±0.028 versus 0.450±0.027, respectively, P=.055).



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  		Figure 7. Cross sections of aortic wall stained with Sirius red for quantitative determination of collagen (x125), in which collagen is displayed in gray tones from dark gray to nearly black (A, control group; B, experimental group). Slight decrease of collagen can be observed in the necrotic area of the vasa vasorum removal group compared with control.


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
The present study confirmed previous observations from our laboratory1 according to which a decrease in the distensibility of the ascending aorta was noted 30 minutes after the removal of the vasa vasorum. Moreover, the present study demonstrated that aortic distensibility was decreased further 15 days after the removal of the vasa vasorum. Along with these functional changes, significant structural abnormalities of the aortic wall were observed 15 days after the vasa vasorum removal. Lack of blood supply to the outer part of the aortic wall is most likely to have accounted for these findings.

Vasa Vasorum Flow of the Aorta
Thin-walled aortas are supplied with nutrients by diffusion from the lumen or from the adventitial vessels. In the thoracic aorta of large mammals, such as humans and dogs, the media exceeds a critical thickness, defined as 29 elastic lamellae, and thus nutrition of the aortic wall is supplemented by blood flow through small vessels, the vasa vasorum, that form a perivascular network and penetrate into the medial layers.3 4 6 7 8 9 Our findings support this concept, since the inner viable zone of the media, which was not affected by the interruption of vasa vasorum supply and was presumably nourished by diffusion from the lumen, had an average width of 28.4 elastic lamellae. For the ascending aorta, the vasa vasorum originate from the coronary arteries; for the aortic arch, mainly from the great vessels of the neck and their proximal branches; and for the descending thoracic aorta, from the intercostal arteries.2 8 Flow through vasa vasorum is subject to active regulation5 7 10 and provides a considerable amount of blood supply to the aortic wall.

Vasa Vasorum Flow and Medial Necrosis
Previous studies from our laboratory1 demonstrated a mild degree of edema in the wall of the ascending aorta 30 minutes after the removal of the vasa vasorum. The present study demonstrated ischemic necrosis, alterations in the elastic tissue of the aortic wall, and a trend for altered collagen-to-elastin ratio 15 days after the removal of the vasa vasorum. Although they are less vulnerable than smooth muscle cells, as the gravity of the changes indicates, elastin fibers were preserved, yet they appeared to a certain extent thinned, flattened, disarranged, and focally fragmented in the areas corresponding to the vasa vasorum removal. These findings are in agreement with previous observations according to which necrosis of the middle third of the media and changes in the elastica of the thoracic aorta were observed after ligation of intercostal arteries in dogs.8 Similar changes secondary to ischemia were found in the carotid arteries of experimental animals.19

Previous investigators have also suggested that decreased blood flow of the aortic wall during acute hypertension might contribute to aortic media necrosis.7 Our findings correlate well with studies in which an aortic infarction lesion similar to the lesion described in the present report was observed in the central zone of the media of the ascending aorta in patients with dissection. The authors suggested that this lesion is related to lack of sufficient blood supply.20

Vasa Vasorum Flow and Functional Abnormalities of the Aorta
A progressive decrease in the distensibility of the ascending aorta after the removal of the vasa vasorum was observed in the present study.

Elastic properties of the aortic wall are determined principally by the elastic components of the media. Elastin, collagen, collagen-to-elastin ratio, and smooth muscle cells, as well as composition and amount of extracellular matrix, thickness of the aortic wall, and aortic diameter, play an important role in the determination of the aortic elastic properties.21 22 23 24 25 26 27

Removal of vasa vasorum led to sustained ischemia of the aortic wall, as suggested by the ischemic nature of necrosis observed 15 days after the procedure. Ischemia leads to acute alterations of the elastic components of the aortic wall. The muscle layers, composed of metabolically active cells, are dependent on a steady flow of nutrients for survival and normal function. Indeed, previous studies from our laboratory1 showed a mild degree of interstitial edema in the aortic wall, suggesting possible smooth muscle cell ischemia, 30 minutes after removal of the vasa vasorum. Experimental studies have shown deterioration in left ventricular distensibility after 30 minutes of ischemia of the myocardium.28 Moreover, an early loss of smooth muscle cells, as well as dislodging and disarranging of some elastin fibers in the aortic media of experimental animals, 1 day after ligation of the intercostal arteries was found by other investigators.8 Therefore, it seems reasonable to suggest that inadequate blood supply of the aortic wall leads to acute changes in the elastic components of the aortic wall and alters its elastic properties acutely.

According to the findings of the present study, necrosis of the smooth muscle cells and changes in the elastic fibers of the aortic wall occurred in the media of the ascending aorta 15 days after the removal of the vasa vasorum. Moreover, the collagen-to-elastin ratio, to which more functional significance is attached than to the absolute percentage of each constituent, showed a trend to shift toward higher values, indicating a stiffer vessel. These structural changes, secondary to interruption of vasa vasorum flow, are most likely to have accounted for the late reduction in the aortic distensibility observed in the present study.

Specific Comments: Limitations of the Study
Change in blood pressure is a factor that could have an effect on aortic distensibility. However, changes in blood pressure were not observed throughout the experiment; consequently, this factor could not have accounted for the findings of the present study.

The lack of changes in blood pressure indicates that the deterioration in aortic elasticity was due to nonpassive changes in aortic elastic properties and that the slope of the elasticity line (plot of pressure versus diameter) of the individual animal has been substantially modified. Although elasticity indexes, such as vessel distensibility, when measured in vivo are reliable means for gaining insight into the elastic properties of the vessel, they describe only a specific part of the elasticity line, the one corresponding to the range of pressures encountered in the particular study. As documented by our results, the vessel becomes less distensible and the slope of the elasticity line steeper within the range of pressures encountered in our study (between diastolic and systolic pressure) after vasa vasorum removal. However, because of lack of information regarding the total configuration of the elasticity line, we cannot determine whether the vessel becomes more or less distensible in low pressures after the removal of the vasa vasorum (Fig 8Down). Nevertheless, regardless of the configuration of the curve below a certain point, the significance of our results remains intact because they indicate that under in vivo conditions (without regard to what happens under theoretical conditions), the aorta becomes stiffer, with obvious clinical implications.



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  		Figure 8. Schematic representation of elasticity line before (I) and after (II) vasa vasorum removal. Within a range of pressures encountered in our study (eg, between 50 and 100 mm Hg), the slope of line I becomes steeper after vasa vasorum removal; ie, with the same change in distending pressure, smaller changes occur in aortic diameter. However, below 50 mm Hg, the pressure-diameter curve may have two different hypothetical configurations. It is reasonable to speculate that the vessel becomes less distensible in low pressures as well, following line IIa (interrupted line), the slope of which is steeper than that of line I. However, because of lack of information regarding the total configuration of the elasticity line, the possibility cannot be excluded that this line, at low pressures, has the configuration IIb (dotted line), with a less steep slope indicating a more distensible vessel.

Factors related to manipulations of the experiment other than the removal of vasa vasorum could have an effect on the findings of the present study. This seems unlikely, however, because except for the removal of the periaortic fat network, the animals in the two groups were otherwise manipulated in an identical manner for the same length of time. Moreover, no histological changes were observed in areas beyond the area supplied by the removed vasa vasorum in the experimental group.

Removal of periaortic fat probably removes nerves to the aortic wall, which might reduce smooth muscle cell tone and influence the findings of the present study. The smooth muscle cell contribution to the elastic properties of large arteries is a controversial topic. Some investigators29 30 31 found a decrease in the distensibility of large arteries by smooth muscle cell excitation, whereas others32 33 34 observed a paradoxical increase. This difference in interpretation is due to conditions under which the measurements are made.35 36 37 Nevertheless, as discussed extensively in the literature, the physiological condition when the artery is in situ and the muscle is largely contracting isometrically is reflected by a decrease in the incremental distensibility by smooth muscle cell contraction.29 35 37 38 Thus, reduction of smooth muscle cell tone in our experiments would be expected to increase aortic distensibility. However, any such effect was overcome by the effect of ischemia, which finally resulted in a decrease of aortic distensibility. Nevertheless, any possible contribution of this factor is confined to the acute phase of the experiment.

Removal of a part of the adventitia, per se, could have an effect on the changes in aortic distensibility documented in our study. The contribution of the adventitia to the mechanical properties of the aortic wall is small. However, removal of an additional layer of the aortic wall, no matter how small its contribution to the stiffness of the aortic wall might be, would theoretically be expected to increase and not to decrease distensibility.

Periaortic fibrosis was noted in the group with vasa vasorum removal, and because of the relatively high elastic modulus of collagen, this could contribute to the decrease of the distensibility 15 days after the procedure. However, proliferation of fibroblasts could be induced either by the surgical stripping of the periaortic fat or by the ischemia itself, thus constituting an expression of the underlying abnormal process.

The absence of inflammatory cells in the area of necrosis can be explained by the interruption of circulation to the aortic wall due to the removal of vasa vasorum. The same finding was observed in similar lesions in experimental8 and human studies.20

Vasa Vasorum Flow: Aortic Structure and Function: Clinical Implications
Structural Changes
Since the structural changes demonstrated in our study resemble in many ways those observed in aging aortas,8 39 40 it can be speculated that the degenerative changes that occur with advancing age may be related to impaired nutrition of the aortic wall.

The findings of the present study support the hypothesis that impaired vasa vasorum flow of the ascending aorta may play an important role in the development of medial degeneration in humans.8 Interestingly enough, vasa vasorum are most abundant in the ascending aorta and arch, precisely the segments most susceptible to the development of dissecting aneurysm. Since muscle lesions tend to increase with age, especially after 40 years of age, and in patients with hypertension, they correlate well with the known occurrence of dissecting aneurysms.41 On the other hand, the infarction of the aortic media with histological features very similar to those observed in our study that was found in dissected human aortas was attributed to disruption of the vasa vasorum by the dissection and consequent interruption of vasal supply.20 Nevertheless, even if aortic infarction follows rather than precedes dissection, it can be speculated that the necrotic zone would constitute a nidus for continuing or future dissections.20 In the same studies, the necrotic zone was more extended when thrombus or atheromata were obstructing the false lumen, which, after the dissection, maintained the media bordering the dissection tract by diffusion of the nutrients. Accordingly, although this was not described in these studies, one might suppose that extensive atherosclerotic lesions of the inner aortic wall would disturb diffusion of nutrients from the true lumen and induce necrosis.

With regard to aortic dilatation, it can be suggested that the weakening of the media by these structural changes would result in disturbed absorption of the hemodynamic forces that act on the wall, which in turn will eventually lead to aortic dilatation. Further, this process may in turn set up a vicious circle of events (including the occurrence of dissection) because, according to Laplace's law, wall tension increases proportionally with arterial radius.42

It is also possible that the lesions observed in the aortic media in syphilitic aortitis are produced by the impairment of blood supply through the thickened, narrowed, and often obstructed vasa vasorum.43

Functional Changes
Changes in vasa vasorum flow may occur in several conditions,7 10 such as hypertensive crisis, decreased cardiac output or shock, congestive heart failure, vasoconstriction or vasodilation due to neurohumoral activation, and administration of pharmacological agents. Vasa vasorum flow may also be compromised after cardiac surgery.

Studies from our14 16 44 45 and other46 47 48 laboratories have shown that aortic distensibility is unfavorably affected in the presence of coronary artery disease. Apart from the mechanical effect of aortic wall atheromata, abnormal nutrition of the aortic wall could be another possible explanation for this finding, since the vasa vasorum for the ascending aorta originate from the coronary arteries.

It has been demonstrated15 49 that aortic distensibility is reduced in hypertensive patients, and it has also been shown that chronic hypertension significantly decreases the vasodilatory capacity of vasa vasorum to the thoracic aorta.5 Accordingly, it is reasonable to speculate that a possible contributing mechanism to the reduced aortic elasticity of hypertensive patients might be reduced vasa vasorum flow.

Thus, under certain conditions, alterations of the elastic properties of the aorta may occur after acute or chronic changes in vasa vasorum flow.

Aortic Distensibility
Several studies have shown that aortic distensibility is an important factor determining left ventricular performance50 51 52 and coronary blood flow.46 53 Coronary flow, and especially subendocardial flow, is reduced in cases of decreased distensibility.53 Moreover, decreased aortic distensibility may contribute to left ventricular dysfunction and dilatation in patients with aortic regurgitation.54

Present technology allows accurate evaluation of the elastic properties of the aorta.13 14 15 16 44 45 46 47 48 49 54 55 Thus, abnormal elastic properties of the aorta may provide an indication of early disease process, and changes of the elastic properties of the aorta may provide information for the natural history of the disease.54 In addition, measurements of aortic distensibility after therapeutic interventions15 16 may further our understanding of the function of the aorta in disease states.

In conclusion, removal of the vasa vasorum network led to an acute decrease in the distensibility of the ascending aorta. In addition, structural changes of the aortic wall and further deterioration of the elastic properties of the aorta were observed 15 days after removal of the vasa vasorum.


*    Acknowledgments
 
This investigation was supported by a grant from the Hellenic Heart Foundation. The authors gratefully acknowledge the advice and constructive comments of Anton E. Becker, MD, in the histological evaluation.

Received November 1, 1994; accepted December 13, 1994.


*    References
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*References
 

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