Aspirin inhibits platelet activity but does not attenuate experimental atherosclerosis

Aspirin inhibits platelet activity but does not attenuate experimental atherosclerosis

Yi-Ping William

Sun, MD, Bo-Qii Zhu, MD, Richard EL Sievers, BS, M. k&erg, PhD, and William W. Parmley, MD San Francisco,

Platelet inhibitors are beneficial in the treatment of atherosclerosis, espe&lly acute ischemic syndromes such as unstable angina and myocardial infarction.‘* 2 Aspirin, which inhibits cyclooxygenase, can prolong bleeding time and decrease platelet aggregation; it has become the best studied, most widely used, and least expensive antiplatelet agent. Fish oil has also been reported to have antiplatelet actions. Ten grams of fish oil per day will alter the biosynthesis of thromboxanes and prostq&ins.3 In addition to inhibition of platelet interaction, fish oil decreases experimental atherosclerosis4 In lipid-fed rabbits, we have shown that fish oil significantly prolongs bleeding time and attenuates the development of atherosclerosis in both the aorta and the pulmonary artery.5 Since both fish oil and aspirin have clinically significant antiplatelet effects, it would seem reasonable that aspirin might also attenuate the development of atherosclerosis. However, recent studies have indicated that aspirin was of little use6-g and may have even enhanced the process of atheroma formation in lhmlthecardimaecularDivisioa,De~tof~eudtbe Cardiov&R lnetitute,univ~~ofcalif~saosan. Supported in pert by the George D. Smith Fund. Received for publication Jxme 24,199% acapted Aug. 1,1%X2. Rep&t requeets: wii w. ParmleY, MD, 11EtLMositt fIasp&& Division of cardiology, hiveraity of calitornia. !&III FM, San l%n&co, CA 94143-0124. 4/l/42146 ooo2-8703/93/$1.00

+ .lO.

CaZ$.

rabbi&l0 Aspirin irreversibly acetylates cyclooxygenase, but it has different inhibitory effects on endogenous thromboxane A2 and prostacyclin biosynthesis at different dosages.” A low dose of aspirin should prevent platelet aggregation by inhibiting the formation of thromboxane A2 more than that of prostacyclin, whereas a large dose that also inhibita prostacyclin production could promote the formation of thrombus.12 Accordingly, the present study was designed to evaluate the dose response effecta of aspirin on bleeding time, platelet aggregation, and atherosclerosis over a wide range of aspirin doses in lipid-fed rabbits. METHODS Study design. Forty-eight msle New Zealand white rabbits (weight, 2.7 to 3.7 kg), which were randomized to five groups (control group C and four treated groups), were fed a 0.3 % cholesterol diet including 3% soybean oil for 12 weeks. Another control group of 10 rabbits received a normal diet without supplementary chole&erol (group N) (Table I). The four treated groups (Al, AlO, A30, and A60) received aspirin by gavage at doses of 1, 10,30, and 60 mgl kg/day, respectively. In preliminary dose-determining dudiea, we achided aspirin in doses of 100 n&kg/day to several rabbits. Consequently, most of them lost their appetites and died. Accordingly, we selected 60 rug/kg/day as the highest dose. The horn4 and high-cholesterol control groupa (groups N and C) were fed only water by gav-

age. Two rabbits that received the dcee of 60 m&g/day lost their appetites and died of dehydration and severe 79

80

Sun et&

Amedcan

Table I. Rabbit groups

GIWp

Number

N

10

C

10

A-l

10 10 10

A-10 A-30 A-60 B-C B-A40

8 9

8

High cholesterol diet * + +

+ +

+ + +

Aspirin (m&kg/day)

Balloon catheter

0 0

-

1 10

-

30 80 0 40

+ +

N, Normal controls; C, choketerol-fed controls; E-C, ballooned, choleeterd-fed controls; B-Am, ballooned rabbits given aspirin 40 -day. *High choleeterol diet: 0.3% choleeterol diet including 3% soybeen oil.

pneumonia All other rabbits were killed 12 weeks later. Since endothelial injury of the aorta can accelerate the processof atherosclerosis,we studied 17additional rabbits with endothelial injury that wasproduced by scrapingthe inner aorta with an inflated balloon at the end of a 5F Fogarty catheter (Baxter Healthcare Corp., Edwards Div., Santa Ana, Calif.). One group of eight rabbits was given aspirin, 40 n&kg/day, and the other group of nine served as controls (Table I). Two of the rabbits that received 40 mglkglday died of dehydration and infection; the rest were killed at an averageof 10.5weeks.All rabbits wereobserved daily for general appearanceand behavior. Body weight wasrecorded every 2 weeks. HemaWagk and biechemical analyses. Bleedingtime, circulating platelet aggregates,and serum cholesterol and serum salicylate levels were measuredat the beginning of the study and then at 6-week intervals. The bleeding time was determined after l-minute warming of each rabbit’s ear in a normal salinebath (37” C). A smallstandard prick wasmadein the ear, and macroscopicvesselswere avoided. The time from the initial bleeding to cessationof bleeding was recorded as the bleeding time. A platelet-count-ratio method13wasmod&d and usedfor quantitative determination of circulating platelet aggregates.A solution of 1 x 10M3mol/L adenosinediphosphate was added to a citrated venous blood sample (ratio of adenosinediphosphate solution and blood was 1:lOOO)before stirring. The samplewasdivided into two tubes, onethat contained ethylenediaminetetraacetic acid formalin solution and one that containedethylenediaminetetraacetic acid only. Platelet-rich plasmawascollected after centrifugation. Platelets in both sampleswere counted with standard techniques (Opera& Reference Manual, Cell-Dyn 900 hematology analyzer, Unipath Co., Pittsburgh, Pa.). The platelet aggregateratio was calculated from the platelet count in the two solutions. The higher the ratio, the fewer the platelet aggregates.The serum salicylate level was measured 90 to 120minutes after the administration of aspirin with a Du Pont automatic clinical analyzer (Du Pont Co., Wilmington, Del.). Total serumcholesterol wasmeasured with DART cholesterol reagent (AMSCO, Erie, Pa.) with the DACOS XL analyzers (Coulter Electronics, Hialeah,

January 19iB Hean Journal

Fla.). As a measureof cumulative exposureof arterial walls to cholesterol, the area under the cholesterol-time curve was calculated (cholesterol-weeks). Balloon injury of the aorta. Twenty rabbits were anesthetized with an intramuscular injection of ketamine, 17.2 mg/kg, xylazine, 3.4 mg/kg, and acepromazine,0.6 mg/kg. Under sterile conditions, the right femoral artery, about 1 cm belowthe inguinal ligaments,wasexposedand isolated. A 5F Fogarty catheter was inserted and advanced retrogradely under fluoroscopic guidanceto the transverse aortic arch. After balloon inflation with 0.75 ml contrast media, the catheter waspulled down slowly to its original position and deflated. The procedure took about 15 seconds and was repeated three times. Then the catheter was removed, the femoral artery was ligated, and the incision wassutured. A prophylactive doseof sulfadiazine (30 mg/ kg/day) wasadministeredsubcutaneouslyfor 7 to 10days. Morphologic studies. After intravenous administration of pentobarbitoll30 mg/kg, the aorta wasremovedfrom its origin (2 cm distal to the aorta valve) down to the bifurcation of the internal iliac arteries; the pulmonary artery was isolated from its beginningat the pulmonary valve to a position just above the bifurcation. The vesselswere opened by a linear vertical incision, fixed in a formalin solution for 24 hours,stained with Sudan 4, and photographed. Finally, the percent of intimal surface lesionswasmeasuredquantitatively by estimation of the total number of stained regions in photographs of each artery with a planimeter.14 Two measurementswere taken in a blinded fashion, and average values were obtained. When 20 specimenswere evaluated in a blinded fashion on a secondoccasion,the average difference between the two readings was 1.7 _+0.9% (aorta) and 1.4 t- 1.3% (pulmonary arteries). The averagelesionthicknesswasestimated asfollows. The rolled aorta wascut along the long axis of the aorta. Each aorta and pulmonary artery wasembeddedin paraffin. Five microhistologic sectionswere cut and stained with hematoxylin-eosin. Then intimal lesionthicknesswasmeasured with a graduated reticle in one eyepieceunder a light microscope. Statistical analysis. Resultsare reported asmean +. SD or SEM. Data were analyzed by Student’s t test, analysis of variance, and correlation test. Dunnett’s multiple comparison procedure wasdone amongthe groups. Statistical analysis was processedby Minitab (Minitab Statistical Software, State College,Pa.). Significance wasjudged at p < 0.05.

RESULTS All rabbits exhibited a modest weight gain throughout the experimental period of 12 weeks. Food intake and weight gain in the normal controls (group N) were significantly higher than that in other unballooned lipid-fed groups (food intake, 216 + 34 gm vs 155 & 39 gm; p < 0.091 and weight gain, 0.76 ;t 0.39 kg vs 0.50 + 0.2&g; p < 0.05) (Table II). Although no significant differences in food intake and body weight were found between the ballooned controls

v-125

Aspirin

Number1

and atherosclerosis

81

Table II. Weight gain and food intake Group

Weight gain (pm) Intake (gm)

N

C

Al

Al0

A30

A60

B-C

B-A40

760 f 390

470 + 310*

710 + 310*

460 f 310*

440 f 150*

380 + 220*

790 f 400

670 + 360

216 t 34

153 + 717

148 + 19t

156 + 43t

159 * 345

158 + 30t

171 f 36

141 + 11

No sign&ant differences were found among the lipid-fed Group designations as in table I.

unballooned

groups and between

groups B-C and B-A40. Values are expressed

as means f SD.

*p < 0.05.

fp < 0.001 compared with group N.

Table Ill. Changesin platelet function Group N BT

(set) Before

treatment After treatment PA ratio Before treatment After treatment

C

Al

Al0

A30

A60

B-C

B-A40

62 f 11

58 + 9

60 * 12

59 + 10

55 f 10

55 I!z 8

61 f 6

61 + 11

62 + 8

56 f 11

70 + 24

71 + 9*

82 + 1st

78 + 23*

56 +. 8

76 + 8

0.99 f 0.07

0.92 + 0.09

0.81 + 0.16

0.80 f 0.15

0.90 + 0.21

0.67 f 0.14

0.91 iC 0.22

0.90 + 0.19

0.95 zk 0.11

0.86 k 0.15

0.84 + 0.13

0.87 + 0.23

0.98 CL 0.31

1.04 f 0.15*

0.80 * 0.13

0.75 + 0.17

Values are expressed as means + SD. Group designations BT, Bleeding time; PA, platelet aggregate ratio.

as in Table I.

*p < 0.05. tp < 0.001 compared with control values.

(B-C) and the ballooned aspirin group (B-A40) or among the unballooned lipid-fed rabbits, there was a decreasing tendency for weight gain with increasing doses of aspirin. Studies of platelet function. Bleeding time was progressively prolonged with aspirin up to a dose of 30 mg/kg/day (55 + 10 seconds vs 82 f 16 seconds; p < 0.001) with no further prolongation at 60 mg/kg/ day (55 f 8 seconds vs 78 + 23 seconds; p < 0.05) compared with the control levels (Table III). Although the three lower doses of aspirin directionally prolonged platelet aggregation, only the 60 mg/kg/ day dose produced a statistically significant inhibition of platelet aggregation compared with the control levels (0.67 + 0.14 vs 1.04 + 0.15; p < 0.05) (Table III). Alterations in cholestefol and salicylate levels. Total serum cholesterol showed a similar increase in all of the cholesterol-fed rabbits in this study, but the degree of change appeared to be affected by the aspirin dose. The lesser increase of cholesterol was found in the groups that received higher doses (Table IV). Groups A10 and A60 had a significantly smaller in-

crease in cholesterol than groups C and Al (667 + 328 mg/dl and 620 SE410 mg/dl vs 1041 f 412 mg/dl and 1125 f 435 mg/dl; p < 0.05). The area under the cholesterol-time curve, expressed as cholesterolweeks, was used as a marker of exposure of the artery to an elevated cholesterol level. As seen in Table IV, no significant differences were found between the control group and the unballooned aspirin groups. The low dose aspirin group (Al) had signi6cantly higher values of cholesterol-weeks than groups A30, A60 (8220 t 3250 mg/dl-wk vs 5530 & 1780 mg/ dl-wk and 5320 + 3680 mg/dl-wk; p < 0.05), and group A10 (8220 + 3250 mg/dl-wk vs 4930 t- 1780 mg/dl-wk; p < 0.01). There was also a statistically significant relationship between aspirin dosage and serum salicylate levels after 12 weeks (r = 0.939; p < 0.001).

Morphologic studies. There was a statistically significant relationship between lesions in the aorta and pulmonary artery among the unballooned groups (r = 0.729; p < 0.001). The average percent of surface lesions of the aorta and of the pulmonary artery were 23.4 * 17.3% and18.5 + 13.8% inunballoonedcho-

82

Sun et al.

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n

Pulmonary

Janumy 1993 Haatl Journal

artery

0 N

C

Al

A10

A30

A60

B-C B-A40

Groups Fig. 1. Distribution of surface lipid lesions(means k SE). The percent of aorta covered by lipid lesions in the balloonedgroups (groupsB-C and B-A40) wassignificantly greater than that in the lipid-fed unballoonedgroups 0, < 0.001). Group Al had a greater percent involvement than the other unbaIloonedgroups (group Al vs A10 and A60; p < 0.05and Al vs C and A30; p < 0.01). The percent of pulmonary artery covered by lipid lesionsin group C washigher than that in groupsA30 and A60 (p < 0.05), whereasit wasgreater in group Al than in the other unballoonedaspirin groups (p < 0.01). No significant difIerences existed between groups B-C and B-A40. Group designationsas in Table I.

Tabk IV. Serum cholesterol and cholesterol-weeks Group N

C

Al

Before treatment

44 + 16

39 + 16

35 + 8

After

36 +- 23

1080 + 407

1160 rt 437

7110 + 2640

8220 f 3250

CH bddl)

treatment CH-W 440

zk 121

A30

A10 27

f 11

694 f 332* 4930

f 178Ot

A60

B-C

B-A40

36 + 12

32 + 19

14 f 21

58 f 14

849 f 375

652 f 418*

770 k 423

982 it 331

5530 f 178Ott

5320 + 368Ott

8470

+ 4210

7220

+ 2160

b&l-wk) No diimmea ware found between groupa B-C and B-A40. Values are expressed BS meana + SD. Group designations c and the unballoouad aspirin groups. CH, Cholesterol lewd; CH- W, cholesterol-weeks. l p < 0.06 compared with group C or Al. fp < 0.01 compared with gmup Al. tfp < 0.05 compared with group Al.

lesterol-fed rabbits; and 76.5 f 11.7% and 11.0 f 8.9% in groups B-C and B-A40 (Fig. 1). No lesions were found in the group that received a normal diet. In the ballooned groups, balloon damage of the endothelium accelerated the development of atherosclerosis, with a greater percentage of aortic ath8rosclerotic plaque than that Been in the rabbit8 that did not undergo balloon damage (76.5 f 11.7% vs 23.4 -+ 17.3% ; p < 0.001). Aortic involvement in groups

aa in Table I. p Q NS between group

A30 and A66 tended to be less but was not statistically different from the control group C (15.6 it 10.0% and 16.1 + 14.6% vs 19.4 + 12.2%; p = NS). Group Al with the lowest dose of aspirin (1 mg/kg/ day) had significantly more atherosclerotic lesions than the other unbahooned groups (Al vs C, A30, p < 0.01 and Al vs AlO, A6@ p < 0.06 in aortaq and Al vs other aspirin groupe; p < 0.01 except compared with group C; p = NS, in pulmonary artery). Athero-

Volume125 Number1

Aspirin and atherosclerosis

0-b

8

0

I

I

2000

4000

I

6000

I

8000

83

I

10000

Cholesterol-weeks (mg/dl-week) Fig. 2. Comparison of cholesterol-weeks and percent aortic lesions among the groups (means f SE). Group designations as in Table I.

sclerotic involvement of the pulmonary artery in the control group C was higher than that in groups A30 and A60 (22.4 + 12.2% vs 10.4 f 8.3% and 9.6 + 11.5% ; p < 0.05). The mean lesion thicknesses at an average of 10.5 weeks in the aorta and pulmonary artery were 0.23 + 0.08 mm and 0.04 + 0.04 mm in group B-A40 and 0.22 f 0.06 mm and 0.05 + 0.05 mm in group B-C. No significant differences in surface lesions and mean lesion thickness existed between the two ballooned groups. In this study, there was a general relationship between aortic atherosclerotic lesions and cholesterolweeks (r = 0.528; p < 0.001). There was no significant reduction by aspirin in percent of lesions in the aorta when plotted against cholesterol-weeks (Fig. 2). DISCUSSION

Platelets appear to play a central role in both the genesis of atherosclerosis and the mediation of acute ischemic events such as unstable angina and myocardial infarction.ry 2 Aspirin produces an irreversible defect in the platelet, which persists for its entire life span. It acetylates the active moiety of cyclooxygenase, which converts arachidonic acid into the prostaglandin cyclic endoperoxides and thus reduces the further transformation of biologically active components. Previous studies have suggested that different doses of aspirin could have different effects on thromboxane A2 and prostacyclin production.15 It has been previously reported that aspirin can retard endothelial regrowth after injury.16 Aspirin has also been shown to attenuate neointimal fibrous

hyperplasia at the anastomoses of prosthetic vascular grafts, presumably by blocking the aggregation and adherence of platelets or by modifying cell proliferation.17 Dipyridamole, 55 mg/day, plus aspirin, 325 mg/day was reported to reduce intimal thickening in dogs with coronary bypass venous grafts.18 The incidence of spontaneous atherosclerosis was reduced by 16% in rabbits that were given dipyridamole and aspirin as compared with those in a control group.lg We evaluated the effects of aspirin on bleeding time and platelet aggregation in cholesterol-fed rabbits and found that aspirin prolonged bleeding time, especially at a dose of 30 mg/kg/day, but only the highest dose of 60 mg/kg/day significantly inhibited platelet aggregation. These studies are in general agreement with those that were previously published, including clinical studies. Boysen et a120 noted evidence of platelet inhibition in patients who received low doses of aspirin. Wu et a1.12 found different effects on platelet thrombus formation between low and high doses of aspirin. All of these data suggest that cyclooxygenase in platelets is more sensitive to inhibition by aspirin than cyclooxygenase in the vascular wall. Low-dose aspirin inhibits thromboxane A2 production in platelets, whereas a large dose inhibits the production of both thromboxane A2 and prostacyclin in endothelial cells. Thus a daily 50 mg dose of aspirin decreased the formation of thromboxane A2 more than prostacyclin in patients with atherosclerosis21 It may be that any dose of aspirin inhibits the formation of both compounds,22 but

84

Sun et al.

thromboxane A2 biosynthesis is more selectively inhibited at a dose of 20 mg/day than a dose of 2600 mg/day.ll This has led to recommendations of low doses of aspirin for patients with coronary artery disease.23p 24 Low doses of aspirin have also been preferred because of lesser toxicity but equivalent therapeutic efficacy.20* 25-28 Utilizing a wide range of aspirin doses in lipid-fed rabbits (1 to 60 mg/kg/day), we could not demonstrate any beneficial effect of aspirin on the development of atherosclerosis. The results even suggested that low-dose aspirin (1 mg/kg/day) promoted atherosclerosis. Much of this effect may have been due to a higher cholesterol level in this group than in the other aspirin groups, At higher doses, still no apparent protection against the development of atherosclerosis was found compared with the control group. It is unclear why there was a decreasing serum cholesterol level with increasing aspirin doses in this study, although it may have been due to suppression of appetite by aspirin. We studied two different models, since it is possible that platelets may not play an equal role in each model, and therefore antiplatelet drugs may not have the same effect. The first model consisted of a high-lipid diet, which leads to the development of the equivalent of fatty streaks filled with foam cells. The second model consisted of damaging the endothelium by withdrawing an inflated balloon the length of the aorta. This latter model should accentuate the interaction of platelets with the aortic wall and therefore might provide a different response to antiplatelet agents. In neither case, however, were we able to demonstrate a beneficial effect of aspirin on the development of atherosclerosis. Our data suggested that groups A30 and A60 had fewer lesions in the pulmonary artery than did the control group. It is possible that the pulmonary artery may be more susceptible to aspirin. Aspirin may have different pharmacologic effects in different vessels. For example, one previous study suggested that aspirin significantly decreased atherosclerosis in the coronary arteries but not in the aorta.2g In other studies, although aspirin significantly decreased thromboxane synthesis and platelet aggregation, it did not reduce experimental atherosclerosis in cholesterol-fed rabbits. On the other hand, indomethatin, phenylbutazone, flufenamic acid, and oxyphenbutazone significantly reduced atherosclerotic plaque formation in cholesterol-fed rabbits.6, 7 Debons et al.1° even found that high-dose aspirin (100 mg/kg) intensified atheromatous plaques in the aorta and coronary arteries. In spite of the apparent lack of efficacy in retard-

American

January 1993 Heat-l Journal

ing experimental atherosclerosis, this should not diminish the role of aspirin in acute ischemic syndromes. Two placebo-controlled trials have demonstrated that the equivalent of one to four aspirin per day can reduce morbidity and mortality by about 50 % in patients with unstable angina pectoris.sOT 3i Similarly, in the ISIS-2 tria127 aspirin was as effective as streptokinase in reducing the overall cardiac mortality rate during acute myocardial infarction, and the combination was even more effective than either drug alone. This has led to the routine practice of giving an aspirin to patients who are experiencing acute ischemic syndromes immediately on arrival in the emergency room. In a previous study we showed that fish oil retarded atherosclerosis and also prolonged bleeding time. The results of this study suggest that the antiplatelet effects of fish oil cannot easily explain its beneficial effects. Fish oil does modify the synthesis of thromboxanes and prostacyclins and shifts the balance of these two substances toward prevention of atherosclerosis.32-36 Fish oil is effective in reducing triglycerides37j38 but is less effective in decreasing cholesterol.5v 3gFish oil may also have some effects on blood rheology,40, 41immune reactions,42 platelet factor 4 /3-thromboglobulin, growth factors and leukotrienes.43 It should also be noted, however, that the effects of fish oil on platelet function were minimal in volunteers.44p45 However, there is still strong evidence from epidemiologic studies, which suggests that a moderate intake of fish oil does have associated benefits relative to the prevention of coronary artery disease.46y47 Certainly our data suggest that there must be other mechanisms involved rather than simple prolongation of bleeding time, which was the same in our studies with fish oil and aspirin. In conclusion, our study suggests that although aspirin has antiplatelet effects, it did not significantly attenuate atherosclerosis in two different models in cholesterol-fed rabbits. We thank Paul E. Sumner for invaluable platelet aggregation studies.

assistance in the

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24. Hariley SP, Cockbill SR, Bevan J, Heptinstall S. Differential inhibition by low-dose aspirin of human venous prostacyclin synthesis and platelet thromboxane synthesis. Lancet 1981;1:969-71. 25. Frishman WH, Miller KP. Platelets and antiplatelet therapy in ischemic heart disease. Curr Probl Cardiol 1986;11:69-136. 26. UK-TIA Study Group. United Kingdom transient ischemic attack (UK-TIA) aspirin trial: interim results. Br Med J 1988;296:316-20. 27. ISIS-II (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of SUSpetted acutemyocardial infarction: ISIS-II. Lancet 1988,2:34960. 28. Pedersen AK, FitzGerald GA. Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase. N Engl J Med 1984;311:1206-11. 29. Pick R, Chedlak J, Glick G. Aspirin inhibits development of coronary atherosclerosis in Cynomolgus monkeys (Macaca Fascicularis) fed anatherogenicdiet. J Clin Invest 1979;63:15862. 30. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, Sackett DL, Sealey BJ, Tanser PH. Aspirin, Sulfinpyrazone, or both in unstable angina: result of a Canadian multicenter trial. N Engl J Med 1985;313:1369-75. 31. Lewis HD, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina: result of a Veterans Administration Cooperative Study. N Engl J Med 1983;309:396403. 32. Kromhout D, Bosschieter EB, de Lezenne Coulander C. The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 1985; 312:1205-g. 33. Shekelle RB, Missell L, Paul 0, Shryock AM, Stamler J. Fish consumption and mortality from coronary heart disease. N Engl J Med 1985,313:820-4. 34. Hirai A, Terano T, Tamura Y, Yoshida S. Eicosapentaenoic acid and adult diseases in Japan: epidemiological and clinical aspects. J Intern Med 1989;225(suppl):69-75. 35. Knapp HR, Reilly IAG, Paola A, FitzGerald GA. In vivo indexes of platelet and vascular function during fish-oil administration in patients with atherosclerosis. N Engl J Med 1986;314:937-42. 36. Bang HO, Dyerberg J. The bleeding tendency in Greenland Eskimos. Dan Med Bull 1980;27:202-5. 37. Lang CA, Davis RA. Fish oil fatty acids impair VLDL assembly and/or secretion by cultured rat hepatocytes. J Lipid Res 1990;31:2079-86. 38. Dallongeville J, Boulet L, Davignon J, Lussier-Cacan S. Fish oil supplementation reduces P-very low density lipoprotein in type III dysbetalipoproteinemia. Arterioscler Thromb 1991; 11:864-71. 39. Holub BJ. Dietary fish oil containing eicosapentaenoic acid and the prevention of atherosclerosis and thrombosis. Can Med Assoc J 1988;139(supplI):377-81. 40. Yetiv JZ. Clinical applications of fish oils. JAMA 1988;260:66570. 41. Cartwright IJ, Pockley AG, Galloway JH, Greaves M, Preston FE. The effects of dietary omega-3 polyunsaturated fatty acids on erythrocyte membrane phospholipids, erythrocyte deformability and blood viscosity in healthy volunteers. Atherosclerosis 1985;55:267-81. 42. Bolton-Smith C, Gibney MJ, Gallagher PJ, Jewel1 R, Hillier K. Effect of polyunsaturated fatty acids of the n-3 and n-6 series on lipid composition and eicosanoid synthesis of platelets and aorta and on immunological induction of atherosclerosis in rabbits. Atherosclerosis 1988;72:29-35. 43. Mueller BA, Talbert RL. Biological mechanisms and cardio-

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of eicosapentaenoic acid into membrane phospholipid pools. Clin Sci 1985:68:449-54. 46. Gramenzi A, ‘Gentile A, Fasoli M, Negri E, Parazzini F, La Vecchia C. Association between certain foods and risk of acute myocardial infarction in women. Br Med J 1990;300:771$ 47. Kristensen SD, Schmidt EB, Dyerberg J. Dietary supplementation with n-3 polyunsaturated fatty acids and human platelet function: a review with particular emphasis on implications for cardiovascular disease. J Intern Med 1989;225(suppl):14150.

Coronary artery ectasia (CAE) is the saccular or fusiform dilatation of a coronary artery. CAE is found in 1.2% to 4.9% of patients at autopsy or during angiegraphic studies, with a similar prevalence of CAE found in patients with atheroscierottc pedpbrai vascular disease (PVD). Abdominal aortic aneurysm (AAA) and CAE are sirniiar in pathogenesis and histoiogy. To determine whether CAE occurs more frequently in patients with AAA than in occlusive forms of atherosclerotic PVD, a review of coronary angbgmms was performed in patients who underwent cardiac catheterization and vascular reconstruction for AAA or occlusive atherosclerotic PVD of the lower extremities. Of 72 patients with AAA, 15 had CAE (20.8%) compared with only 2 of 89 patients with atherosclerotic PVD (2.9%) @ < 0.003). CAE was pradominantiy discrete, located in the left coronary system, and associated with significant coronary atherosclerosis. CAE may be more prevalent in patients with AAA resulting from a similar pathogenetic process. (AM HEART J

1993;125:88.) MAJ Karl C. Stajduhar, MD,” MAJ John R. Laird, MD,b MAJ Kevin M. Rogan, MD,b and COL Dale C. Wortham, MDb Z’acoma, Wash., and Washington, D.C.

Coronary artery ectasia (CAE) is the angiographic or postmortem finding of abnormal coronary arterial dilatation, the diameter of which exceeds by 1.5 times an adjacent normal segment. Two subtypes of CAE have been described: discrete (saccular) aneurysms From &the Cardiology

Service, Madigan Army Medical Center, and bthe Cardiology Service, Walter Reed Army Medical Center. The opinions or assertions contained herein are the private views of the authors and are not to he construed as official or as reflecting the views of the Department of the Army or the Department of Defense. Received for publication April 3, 1992; accepted July 28, 1992. Reprint requests: Dale Wortham, MD, Cardiology Service, Walter Reed Army Medical Center, Washington, DC 20307-5001. 4/l/42168

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(Fig. 1) and fusiform (ectatic) aneurysms (Fig. 2).le3 Various studies have reported the incidence of CAE in a series of autopsy or angiographic examinations to be 1.2 % to 4.9% .l, 4-g CAE and abdominal aortic aneurysm (AAA) share similar histologic features,3, 4, lo and controversy exists as to whether there is an increased association between CAE and AAA.3-6~ i1 The largest angiographic series of CAE was derived from the Coronary Artery Surgery Study registry, which reported a 4.9% incidence of CAE.5yg In this study there was no increased incidence of CAE noted in patients with atherosclerotic peripheral vascular disease (PVD), although subgroups of patients with AAA were not analyzed. A lack of correlation between 000%8703/93/$1.00

+ .lO.