Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis

Rheologic analysis of gastric mucosal hemodynamics in cirrhosis

Rheologic analysis of gastric mucosal hemodynamics in patients with cirrhosis Eiichi Masuko, MD Hisato Homma, MD Hidetoshi Ohta, MD Shuuichi Nojiri, MD Ryuzo Koyama, MD Yoshiro Niitsu, MD

Background: Portal hypertensive gastropathy causes some gastric mucosal microcirculatory disorders in cirrhotic patients, but the nature of the rheologic dysfunction in the gastric microcirculation remains to be clarified. Methods: To examine the rheologic properties of the gastric microcirculation, we subjected 112 cirrhotic patients and 51 control subjects to endoscopic laser Doppler flowmetry and measured multiple variables of flow, red blood cell volume, and velocity. Furthermore, based on these results, we analyzed the shear rate which reflects the status of the microcirculatory system. To validate the laser Doppler flowmetry, we derived the relationship between red blood cell volume and cross-

Received October 20, 1997. For revision April 28, 1998. Accepted October 21, 1998. From the Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo; Department of Gastroenterology, The Shinnittetsu Muroran General Hospital; and the Department of Internal Medicine, Hokkaido Kitano Hospital, Muroran, Japan. Reprint requests: Yoshiro Niitsu, MD, PhD, Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku Sapporo 060 Japan. Copyright © 1999 by the American Society for Gastrointestinal Endoscopy 0016-5107/99/$8.00 + 0 37/1/95336 VOLUME 49, NO. 3, PART 1, 1999

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sectional areas of submucosal collecting venules; near-infrared endoscopy was used to evaluate this relationship. Results: Analysis of shear rate according to the severity of portal hypertensive gastropathy showed that the mucosa was exposed to strong hemokinetic stress in severe cases, characterized by a higher shear rate than in control subjects or in mild cases. Nitroglycerin, administered by intravenous infusion (1.0 µg/kg/min), reduced blood flow and restored shear rate to control levels in patients with severe portal hypertensive gastropathy. Conclusion: This rheologic study of the gastric mucosa suggests that a disorder of the shear rate control mechanism in the microcirculation is associated with severe portal hypertensive gastropathy. Gastric mucosal lesions are known to occur widely in cirrhotic patients as either a complication of portal hypertension (PHT) or a metabolic disorder,1-13 and the study of their pathogenesis has focused on the relationship between the hepatic and gastric circulations. Portal hypertensive gastropathy (PHG) is one type of such gastric mucosal lesions that sometimes causes lethal hemorrhage resistant to therapy. The pathogenesis of PHG is poorly understood, and its treatment needs to be improved. Much effort has been devoted to the clarification of gastric mucosal hemodynamics in cirrhotic patients and the pathogenesis of PHG.1-14 Nevertheless, some controversies remain.3-13 First, it is unclear whether gastric mucosal blood flow (GMBF) increases or decreases in patients with cirrhosis. Second, it is not clear how the GMBF is involved in the pathogenesis of PHG and whether it should be used as the most accurate index of severity. Many studies have reported values for the GASTROINTESTINAL ENDOSCOPY

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Table 1. Background data for control subjects and patients with cirrhosis Parameter

Control

Cirrhosis

Numbers Gender (M/F) Age (yr) Hemoglobin (gm/dL) Hematocrit (%) Mean arterial blood pressure (mm Hg) Heart rate (beats/min) Child’s grading A B C

51 27:24 51.8 ± 10.7 13.0 ± 2.1 40.8 ± 3.2 95 ± 15

112 55:57 60.4 ± 12.1* 11.0 ± 1.6* 32.8 ± 3.7* 91 ± 10

72 ± 18

74 ± 16 32 44 36

Values are expressed as means ± SD (standard deviation). *Significantly different by Welch’s t test (p < 0.05).

A

B

GMBF associated with PHG,3-8 but there are few studies regarding rheologic parameters in patients with cirrhosis such as the shear rate, which reflects endothelial-dependent microcirculatory regulation and homeostasis.15-23 In addition, little is known concerning the rheologic effect that nitroglycerin, a vasodilator, exerts on the gastric mucosal microcirculation, although it has recently been used for treatment of PHT.24-28 To elucidate these issues, we measured gastric mucosal hemodynamics in cirrhotic patients by laser Doppler flowmetry (LDF). We analyzed three variables that reflect the gastric mucosal microcirculation in cirrhosis: volumetric flow, red blood cell (RBC) volume, and RBC velocity. From these data, wall shear rate was calculated based on a mucosal microvasculature model. Furthermore, the effects of nitroglycerine on the shear rate of gastric mucosal microcirculation were studied. The use of LDF has been questioned with regard to its validity, reproducibility, and non-linearity of measurements. To ensure the reliability of the LDF measurement, near-infrared endoscopy was concomitantly performed to observe dark spot areas21,22 as an estimation of a mucosal hemodynamic parameter, specifically the RBC volume. PATIENTS AND METHODS

C Figure 1. Scheme of site selection and measurement areas for LDF and near-infrared endoscopy. A, Area in which dark spots are measured by near-infrared endoscopy under indocyanine green injection. x, Point measured by LDF. B, LDF. C, Dark spots by near-infrared endoscopy. The white ruler was scaled in millimeters and also used for the calibration of the near-infrared light measurement system. 372

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The study population included 112 histologically confirmed cirrhotic patients and 51 noncirrhotic control subjects who were admitted to the Shinnittetsu Muroran General Hospital. The etiology of cirrhosis was alcoholic hepatitis in 12 patients and viral hepatitis in the remaining patients. Noncirrhotic control subjects consisted of 13 patients with chronic viral hepatitis and 38 healthy volunteers. The study protocol was approved by the institutional review board of the hospital. Patients VOLUME 49, NO. 3, PART 1, 1999

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gave their written consent to participate after explanation of the nature and purpose of the study. The background profile of patients and control subjects is summarized in Table 1. Measurements of gastric mucosal blood flow All subjects were premedicated with intramuscular injection of prifinium bromide (7.5 mg) after an overnight fast,24 and underwent upper GI endoscopy. During endoscopy (Fujinon EG7-HR2; Fuji Photo Optical Co., Ltd., Omiya, Japan), we kept air insufflation to a minimum and the room temperature at 22.1°C. LDF was performed with a laser Doppler perfusion monitor (BPM403A; TSI Inc., St. Paul, Minn.) and an endoscopic fiberoptic probe that can simultaneously monitor blood flow, mean RBC velocity, and RBC volume. The LDF probe was passed through the accessory channel and was placed in gentle contact with the gastric mucosa of the antrum, the distal body, and near the cardia (fornix) along the greater curvature. Ideally, the LDF probe should be placed perpendicular to the mucosal surface. However, our preliminary experiment with oral mucosa showed that the LDF signal did not significantly change if the probe angle was kept within 30 degrees of perpendicular. As long as the probe angle was kept within this range, the measurement error was considered negligible in the study. The LDF probe was placed as vertical to the surface as possible, although it was not possible to measure the probe angle with the gastric mucosa. Measurements were taken using a thermal array recorder (RTA1200M; Nihon Kohden Co., Ltd., Tokyo, Japan). To provide a steady state for accurate recording at each point, the subjects were instructed to hold their breath for 10 seconds throughout the recording procedure. All endoscopic procedures and measurements were performed by the same endoscopist who was blinded to the results obtained during data acquisition. Nitroglycerine was administered by continuous intravenous infusion (1 µg/kg/min) for approximately 8 minutes after initial data acquisition. Blood pressure and heart rate were monitored intermittently during endoscopy, whereas successive LDF was performed at a fixed point near the cardia (fornix). When a steady state was established, the second set of data was acquired. Site selection and data processing The site for measurement was selected to meet the condition that, when examined at endoscopy, the mucosa was found to have a homogeneous surface, with neither superficial nor submucosal hemorrhages. Near-infrared endoscopy of the site was performed within a circle with a radius of 2 cm and the average of cross-sectional areas of submucosal collecting venules within the circle was calculated. LDF was obtained at five points within the circle, and the average of these measurements was taken as the representative value of the site. Because the directly obtained LDF data contained high-frequency noise, they were processed and smoothed by 5-second time average filtering at each point. The site selection is schematically shown in Figure 1. VOLUME 49, NO. 3, PART 1, 1999

Figure 2. Imaginary vessel and parameters of gastric mucosal hemodynamics. Near-infrared endoscopy Before nitroglycerine administration, indocyanine green (0.5 mg/kg) was administered intravenously. Nearinfrared endoscopy can visualize submucosal blood vessels (collecting venules) enhanced by indocyanine green, with their cross-sections being recognized as “dark spots.”29,30 The near-infrared endoscopy system consists of two units29: an infrared electronic endoscope (Fujinon EG7-HR2; Fuji Photo Optical Co., Ltd., Omiya, Japan) with its infrared cut filter removed and an image processing unit (Nexus 6800; Nexus Co., Tokyo, Japan). The light source was a high-output diode laser with a wavelength of 805 nm, an output of 200 mW, and a band width of 30 nm. The light was guided by a quartz optical fiber through the accessory channel of the endoscope.29,30 Calculation of variables Flow, RBC volume, and RBC velocity were directly measured by LDF. These three variables were used in the following formula: flow ∝RBC volume × RBC velocity. Each variable was measured in volt units. LDF can monitor the mean RBC velocity and the RBC volume in the columnar region with a constant depth (minute length; dL) (approximately 1 mm)31,32 (Fig. 2). It has been demonstrated that the course of gastric mucosal capillaries is almost vertical to the surface33 which makes it possible to obtain RBC volume ∝ (Σ ai) × dl, where ai is the cross-sectional area of a GASTROINTESTINAL ENDOSCOPY

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Table 2. Grading of improvement in gastric mucosal endoscopic findings due to nitroglycerin Improvement of endoscopic findings Disappearance or decrease of superficial oozing Decrease in mucosal redness No change or worsening of redness

Grade 2 1 0

A higher grade was assigned if two endoscopic findings were recognized.

We define Rj as the vascular radius of gastric submucosal collecting venules ( j) within the circle of interest ( j = 1,2...,N); the following formula is given according to Murray’s law.21,22 Rj3 = rj13 + rj23 +... + rjn3 = nj · rj03 where rji (i = 1,2,...,nj) is the vascular radius of the mucosal capillary ji, connected to venule j, and rj0 is the mean of rji (i = 1,2,...,nj). The sum from venule 1 to venule N is expressed as follows: R13 + R23 +... + RN3 = n1 · r103 + n2 · r203 +... + nN · rN03 Figure 3. Correlation between RBC volume by LDF and dark spot area by near-infrared endoscopy.

capillary “i” in the region. From this formula, we evaluated the mean cross-sectional area of capillaries in the gastric mucosa of interest by measuring the RBC volume. As an index of shear stress,16 we defined the pseudo-wall shear rate of mucosal vessels as follows: pseudo-wall shear rate = RBC velocity / (RBC volume)1/2 based on the gastric mucosal model.33 This variable is measured in units of volt1/2. Poiseuille’s law is assumed to apply based on prior studies.15,16,33 The formulas are summarized in Fig. 2. PHG severity and endoscopic improvement by nitroglycerine The severity of PHG in cirrhotic patients was assessed and classified into no PHG, mild PHG, or severe PHG after the classification of McCormack et al.12 When nitroglycerine administration ameliorated mucosal hyperemia, the degree of improvement in the mucosa identified by endoscopy was classified and evaluated (Table 2). Correlation between LDF and near-infrared endoscopy There are several reports on the problems associated with LDF.34-36 In addition to the stability and the reproducibility of measurements, the non-linearity between the RBC volume and the Doppler signal from the mucosa may cause underestimated results in cases of higher RBC volume.35 To support the validity of LDF measurements, we used near-infrared endoscopy as an additional method for the estimation of RBC volume. The relationship between RBC volume and the cross-sectional area of the sub-mucosal venules is derived as follows: 374

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This leads to N · R03 = M · r03 where R0 is the mean radius of collecting venules, r0 is the mean radius of capillaries, and M is the number of capillaries in the region of interest. It follows that A0 = (M/N)2/3 · a0 where A0 is the mean area of collecting venules measured by nearinfrared endoscopy and a0 is the mean area of capillaries which we expect to be proportional to the RBC volume measured by LDF. Statistical analysis Because the data were assumed to be of normal distribution, Welch’s test, paired t test, or one-way analysis of variance (ANOVA) with Duncan test were used. When two factors were to be considered, repeated measure ANOVA was done. Fisher’s exact probability test was performed as a proportion test. In principle, values were expressed as means ± SD (standard deviation) unless otherwise specified. Significance was established at p < 0.05 by two-tailed test whenever possible.

RESULTS Effects of background on gastric mucosal hemodynamics There were differences in age, blood hemoglobin concentration, and hematocrit level between cirrhotic patients and control subjects (Table 1), but we found no significant correlation between these and the other hemodynamic parameters (data not shown). In cases with severe anemia, low hemoglobin concentration (< 7.5 gm/dL) or low hematocrit level (< 25%) reduced the RBC volume in the gastric mucosa in preliminary LDF measurements. However, in this VOLUME 49, NO. 3, PART 1, 1999

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Table 3. Pseudo-wall shear rate (volt1/2) in gastric mucosa of control subjects and patients with cirrhosis n Control All patients with cirrhosis No PHG Mild PHG Severe PHG

51 112 33 44 35

Antrum 0.73 0.78 0.81 0.84 0.77

± ± ± ± ±

0.20 0.31 0.24 0.33 0.29

Corpus 0.69 0.79 0.80 0.94 0.78

± ± ± ± ±

0.21 0.28 0.23 0.24 0.19

Fornix 0.81 1.18 0.95 0.98 1.55

± ± ± ± ±

0.29 0.32* 0.27 0.22 0.33*

Values are expressed as means ± SD. PHG, Portal hypertensive gastropathy. *Significantly higher by repeated measure ANOVA.

study, hemoglobin ranged from 8.7 to 15.5 gm/dL and hematocrit from 26.0% to 44.9%. Correlation analysis in all subjects showed that there was no significant relationship between hemoglobin or hematocrit and the RBC volume in this population. Correlation between LDF and infrared endoscopy The scattergraph (Fig. 3) showed a strong positive correlation between the cross-sectional area of venules calculated by near-infrared endoscopy and the RBC volume measured by LDF. The correlation coefficient was 0.86 (p < 0.01). Wall shear rate of gastric mucosa in control subjects and patients with cirrhosis Among the control subjects, the shear rate was 0.73 ± 0.20 volt1/2 at the antrum, 0.69 ± 0.21 volt1/2 at the body, and 0.81 ± 0.29 volt1/2 at the fornix (Table 3). We found no difference in wall shear rates based on gastric site. In all patients with cirrhosis, the shear rate was 0.78 ± 0.31 volt1/2 at the antrum and 0.79 ± 0.28 volt1/2 at the body, a statistically negligible difference. However, a multiple comparison among the sites in all cirrhotic patients showed an increased shear rate (1.18 ± 0.32 volt1/2) at the fornix where PHG is often recognized. In the patients with mild or no PHG, shear rates were the same at all sites, but a higher shear rate (1.55 ± 0.33 volt1/2) was observed at the fornix in patients with severe PHG. Multiple comparisons revealed that the wall shear rate was higher at the fornix in patients with severe PHG than in those with mild or absent PHG. Influence of PHG severity on blood flow and wall shear rate The mean baseline values of flow (0.58 volt1/2) or shear rate (0.81 volt1/2) in control subjects were used to classify cirrhotic patients into two groups (high/low flow or high/low shear rate). The patients with severe PHG were distributed on the scattergraph independently of the amount of flow. However, according to the shear rate criterion, 82% VOLUME 49, NO. 3, PART 1, 1999

Figure 4. Scatter diagram of RBC velocity and RBC volume of GMBF in cirrhosis. No PHG, n = 33; PHG mild, n = 44; PHG severe, n = 35. Hyperbolic curve: RBC velocity = k1x (RBC volume)–1; k1 = 0.58. Square root curve: RBC velocity = k2x (RBC volume)1/2; K2 = 0.81. Flow corresponds to the coefficient k1 of the hyperbolic curve on the RBC volumevelocity graph. Similarly, shear rate corresponds to the coefficient k2 of the square root curve. Most severe PHG patients distribute above the mean shear rate curve for control subjects but scatter randomly around the mean flow curve.

of patients with severe PHG were included in the higher shear rate group (Fig. 4). Nitroglycerine effects on mucosal shear rate in PHG After nitroglycerine administration, wall shear rate at the fornix did not change in control subjects. Also, in patients without PHG or mild PHG, there GASTROINTESTINAL ENDOSCOPY

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Figure 5. Effects of nitroglycerine on pseudo-wall shear rate in gastric mucosa at the fornix in cirrhosis. No PHG, n = 33; PHG mild, n = 44; PHG severe, n = 35. Values are expressed as mean ± SD. *Significantly different from other degrees of severity of PHG by one-way analysis of variance and Duncan test. **Significantly different from controls by Welch’s test. ***Significantly decreased after nitroglycerine by paired t test.

Table 4. Comparison of the incidence of severe portal hypertensive gastropathy in cirrhosis classified by parameters reflecting gastric mucosal hemodynamics PHG(–) or mild PHG Flow <0.58 Volt* >0.58 Volt Total Shear rate <0.81 Volt1/2† >0.81 Volt1/2 Total

Severe PHG

36 41 77

16 19 35

39 38 77

7 28 35

Total 52 60 112

]‡

46 66 112

*The mean value of flow at fornix in control subjects. †The mean value of shear rate at fornix in control subjects. ‡Significantly different by Fisher’s exact probability test (p < 0.01).

was no significant alteration by nitroglycerine, although nitroglycerine reduced velocity and flow in all subjects. In contrast, in patients with severe PHG, the wall shear rate decreased to the control level of 0.84 ± 0.27 from the initial level of 1.55 ± 0.33 volt1/2 (Fig. 5). In addition, to verify whether the shear rate returns to the control level while nitroglycerine improves PHG, we compared the degree of endoscopic improvement with the shear 376

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rate deviation from the control level (Table 5). There was no shear rate deviation, compared with control subjects, in the two PHG groups whose endoscopic findings were ameliorated by nitroglycerine. However, in the PHG group without improvement of the findings, the shear rate remained at a high level which was 1.37 times that of control subjects. Other effects of nitroglycerine On average in all subjects, nitroglycerine reduced the systolic blood pressure by 10 mm Hg, the diastolic blood pressure by 8 mm Hg, and mean arterial pressure by 10 mm Hg. In contrast, heart rate increased by 11 beats/min. As a side effect, transient headache was seen in 16% of control subjects and in 5% of cirrhotic patients. DISCUSSION Many studies have stated the principles of LDF31,32 and its usefulness for clinical microcirculatory analysis.3-8,34 However, several problems concerning the validity of LDF measurements persist.35,36 From our study comparing LDF with nearinfrared endoscopy, we confirmed that RBC volume measured by LDF reflects the cross-sectional area of mucosal capillaries and that LDF is useful in comparing hemodynamics among various subjects. VOLUME 49, NO. 3, PART 1, 1999

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Table 5. Improvement in gastric mucosal endoscopic findings and shear rate deviation from control levels after nitroglycerin in patients with portal hypertensive gastropathy Improvement in endoscopic findings (grade)

n

Shear rate deviation (%)

0 1 2

18 48 13

37 ± 11* 11 ± 12 8 ± 14

Shear rate deviation =

Shear rate after nitroglycerine – Controls’ mean shear rate Controls’ mean shear rate

Values are expressed as mean ± SD. *Significantly higher than the other score groups by one-way ANOVA and Duncan test.

No agreement has been reached as to whether GMBF is increased or decreased in cirrhosis. Iwao et al.5,6,8,13 maintained that the decrease in GMBF causes susceptibility to the gastric mucosa in cirrhotic patients. In contrast, Panés et al.3,4,7,9,10 argued that the increase in GMBF reflects the hyperdynamic circulation recognized in cirrhotic patients. The controversy regarding what role mucosal blood flow plays in the pathogenesis of PHG includes the question of whether the magnitude of flow is the only important factor. This study strongly suggests that not only the magnitude of flow but also the wall shear rate is involved in the pathogenesis of severe PHG. Shear rate is determined by blood velocity and vessel diameter. In general, the vascular endothelial cell is subjected to hemokinetic stress of both pressure and wall shear stress as direct effects of blood flow. Wall shear stress, which is the product of wall shear rate and viscosity, acts as a trigger for endothelial regulation and accommodation. The significance of this fact has recently been recognized15-23 as rheologic studies have been developed. The increase in shear rate makes endothelium produce mediators that alter vascular tone, resulting in a return toward the previous steady state. If the endothelial smooth muscle system is intact, the microcirculation has a robust capacity to control shear stress and maintain this constant by its own negative feedback mechanism.16,22,23 Although the magnitude of GMBF is variable because of factors such as tissue oxygen demand, some rheologic parameters are constant under normal physiologic conditions. This means that we can evaluate the integrity of the gastric mucosal microcirculation by assessment of shear stress, if available. Few studies exist37 concerning the behavior of shear stress in microcirculation in PHT because of the technical difficulties of direct measurement. Therefore we analyzed rheologic behavior using pseudo-wall shear rate calculated VOLUME 49, NO. 3, PART 1, 1999

from variables obtained by LDF based on the gastric mucosal vascular model. The present study showed no relationship between blood flow and PHG severity, but the mucosa with severe PHG was exposed to higher wall shear rate than the mucosa without PHG or with mild PHG. The shear control mechanism is known to continue functioning, even if blood flow is elevated 4 or 10 times.22,23 This suggests that the mucosa still preserves its shear rate-control function in mild PHG but loses this function in severe PHG. However, increased shear stress is reported to elevate endothelial permeability 18 and is thought to damage the endothelium directly in diabetic retinopathy.17 The increased shear rate may be both the result and the cause of the gastric mucosal microcirculatory disorder in severe PHG. As blood flow into the mucosal microvascular system is mainly regulated at the arteriolar level,15 the dysfunction of gastric arterioles is presumably responsible for the regulatory failure and the vascular hyporesponsiveness to catecholamines demonstrated in cirrhotic patients37 may underlie the dysfunction. Nitroglycerine is known to be effective therapy for the acute gastric hemorrhage that occurs in PHG.24 It is believed that either the decreased cardiac output caused by systemic vasodilation by nitroglycerine is directly involved in reduction of splanchnic inflow,25,28 or the reduction of gastric mucosal blood inflow is due to splanchnic arterial constriction induced by a baroreceptor reflex.26,27 Regardless of mechanism, nitroglycerine is believed to reduce the gastric mucosal blood inflow. The most striking finding in our study is that nitroglycerine restored the increased wall shear rate observed in severe PHG to the control levels, concomitant with improvement in endoscopic findings (whereas those of control subjects and patients without severe PHG were not altered by nitroglycerine). From this, it was confirmed that the shear GASTROINTESTINAL ENDOSCOPY

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control mechanism functions normally even when gastric mucosal inflow varies by nitroglycerine in control subjects or patients without severe PHG. In addition, nitroglycerine may alleviate the hemokinetic stress and allow the damaged microcirculation to again regulate blood flow. This study demonstrates that nitroglycerine may improve PHG during short-term administration. However, long-term effects should be considered in regard to the systemic hyperdynamic state in cirrhosis.38,39 Viscosity affects shear stress concomitantly with shear rate and is known to be mainly a function of blood hematocrit level and shear rate.15 Under high shear rate conditions such as in microcirculation, the change of viscosity due to alteration of hematocrit level or shear rate is assumed to be negligible40 compared with the influence of shear rate on shear stress. Therefore, the shear rate in the study is considered to reflect the behavior of wall shear stress. From the study of wall shear rate, we conclude that the regulatory dysfunction and hemokinetic abnormalities in the gastric microcirculation, reflected by the increased shear rate, is associated with severe PHG, and flow magnitude alone may not be a useful index of severity of PHG. Nitroglycerine may improve severe PHG by reducing gastric mucosal inflow with a reduction of hemodynamic stress, although further investigation is required for long-term therapy with nitroglycerine.

6. Kotzampassi K, Eleftheriadis E, Aletras H. Gastric mucosal blood flow in portal hypertension patients: a laser Doppler flowmetry study. Hepatogastroenterology 1992;39:39-42. 7. Ohta M, Hashizume M, Higashi H, Ueno K, Tomikawa M, Kishihara F, et al. Portal and gastric mucosal hemodynamics in cirrhotic patients with portal hypertensive gastropathy. Hepatology 1994;20:1432-6. 8. Sawant P, Bhatia R, Kulhalli PM, Mahajani SS, Nanivadekar SA. Comparison of gastric mucosal blood flow in normal subjects and in patients with portal hypertension using endoscopic laser-Doppler velocimetry. Indian J Gastroenterol 1995;14:87-90. 9. Geraghty JG, Angerson WJ, Carter DC. A study of regional gastric mucosal blood flow in a rat model of hepatic cirrhosis. Am J Physiol 1992;262:G727-31. 10. Piqué JM, Leung FW, Kitahora T, Sarfeh IJ, Tarnawski A, Guth PH. Gastric mucosal blood flow and acid secretion in portal hypertensive rats. Gastroenterology 1988;95:72733. 11. Iwao T, Toyonaga A. “Passive” gastric mucosal congestion in patients with gastropathy. Dig Dis Sci 1993;38:1563-4. 12. McCormack TT, Sims J, Eyre-Brook I, Kennedy H, Goepel J, Johnson AG, et al. Gastric lesions in portal hypertension: inflammatory gastritis or congestive gastropathy? Gut 1985; 26:1226-32. 13. Hasumi A, Aoki H, Shimazu M, Kawata S, Yoshimatu Y. Causative relationship between a hyperdynamic state due to increased A-V anastomosis in the gastric wall and AGML in patients with liver cirrhosis. J Gastroenterol Hepatol 1989;4:143-5. 14. Albillos A, Colombato LA, Enriquez R. Sequence of morphological and hemodynamic changes of gastric microvessels in portal hypertension. Gastroenterology 1992;102:2066-70. 15. Zweifach BW, Lipowsky HH. Pressure-flow relations in blood and lymph microcirculation. In: Renkin EM, Michel CC, editors. Handbook of physiology. Section 2: The cardiovascular system. Volume 4. Microcirculation, Part 1. Bethesda: Am Physiol Soc; 1984. p. 251-307. 16. Koller A, Kaley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol 1991;260:H862-8. 17. Merimee TJ. Diabetic retinopathy. A synthesis of perspectives. N Engl J Med 1990;322:978-83. 18. Jo H, Dull RO, Hollis TM, Hollis TM, Tarbell JM. Endothelial albumin permeability is shear dependent, time dependent, and reversible. Am J Physiol 1991;260:H1992-6. 19. Pries AR, Secomb TW, Gaehtgens P. Design principles of vascular beds. Circ Res 1995;77:1017-23. 20. Hudetz AG, Kiani MF. The role of wall shear stress in microvascular network adaptation. Adv Exp Med Biol 1992;316:31-9. 21. Murray CD. The physiological principle of minimum work I. The vascular system and the cost of blood volume. Proc Natl Acad Sci U S A 1926;12:207-14. 22. Kamiya A, Togawa T. Adaptive regulation of wall shear stress to flow changes in canine carotid artery. Am J Physiol 1980;239:H14-21. 23. Zarins CK, Zanita MA, Giddens DP, Ku DN, Gragov S. Shear stress regulation of arterial lumen diameter in experimental atherogenesis. J Vasc Surg 1987;5:413-20. 24. Noguchi H, Toyonaga A, Tanikawa K. Influence of nitroglycerin on portal pressure and gastric mucosal hemodynamics in patients with cirrhosis. J Gastroenterol 1994;29:180-8. 25. Rector WG Jr, Hossack KF, Ready JB. Nitroglycerin for portal hypertension. A controlled comparison of the hemodynamic effects of graded dose. J Hepatol 1990;10:375-80.

ACKNOWLEDGMENTS We acknowledge the advice and instruction for statistical analysis from Dr. R. Kishi and Professor H. Miyake of the Department of Public Health, Sapporo Medical University. Also, we wish to thank Tiffany M. Taylor for her editorial assistance. REFERENCES 1. D’Amino G, Montalbano L, Traina M, Pisa R, Menozzi M, Span C, et al. Liver Study Group of V. Cervello Hospital. Natural history of congestive gastropathy in cirrhosis. Gastroenterology 1990;99:1558-64. 2. Tanoue K, Hashizume M, Wada H, Ohta M, Kitano S, Sugimachi K. Effects of endoscopic injection sclerotherapy on portal hypertensive gastropathy: a prospective study. Gastrointest Endosc 1992;38:582-5. 3. Panés J, Bordas JM, Piqué JM, Bosch J, García-Pagán JC, Feu F, et al. Increased gastric mucosal perfusion in cirrhotic patients with portal hypertensive gastropathy. Gastroenterology 1992;103:1875-82. 4. Chung RS, Bruch D, Dearlove J. Endoscopic measurement of gastric mucosal blood flow by laser Doppler velocimetry: effect of chronic esophageal variceal sclerosis. Am Surg 1988;54:116-20. 5. Iwao T, Toyonaga A, Ikegami M, Oho K, Sumino M, Harada H, et al. Reduced gastric mucosal blood flow in patients with portal hypertensive gastropathy. Hepatology 1993;18:36-40. 378

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26. Kroeger RJ, Groszmann RJ. The effect of the combination of nitroglycerin and propranolol on splanchnic and systemic hemodynamics in a portal hypertensive rat model. Hepatology 1985;5:425-30. 27. Garcia-Tsao G, Groszmann RJ. Portal hemodynamics during nitroglycerin administration in cirrhotic patients. Hepatology 1987;7:805-9. 28. Blei AT, Gottstein J. Isosorbide dinitrate in experimental portal hypertension study of factors that modulate the hemodynamic response. Hepatology 1986;6:107-11. 29. Ohota H, Kohgo Y, Goto Y, Takahashi Y, Mogi Y, Watanabe N, et al. The near-infrared electronic endoscope for diagnosis of esophageal varices. Gastrointest Endosc 1992;38:330-5. 30. Ohota H, Kohgo Y, Takahashi Y, Koyama R, Suzuki H, Niitsu Y. Computer-assisted data processing of images of mucosal and submucosal vessels of stomach obtained by visible and infrared endoscopy using directional contrast filter. Gastrointest Endosc 1992;8:3430-5. 31. Kiel JW, Riedel GL, DiResta GR, Shepherd AP. Gastric mucosal blood flow measured by laser-Doppler velocimetry. Am J Physiol 1985;249:G539-45. 32. Shepherd AP, Riedel GL, Kiel JW, Haumschild DJ, Maxwell LC. Evaluation of an infrared laser-Doppler blood flowmeter. Am J Physiol 1987;252:G832-9. 33. Tsuchihashi Y. Studies on structure and function of the mucosal microvascular system of the gastrointestinal tract with special references to their relations to epithelial func-

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