Lawrence E. Boerboom

Prevention of lipid accumulation in experimental vein bypass grafts by antiplatelet therapy.

The ameliorative effect of antiplatelet therapy on atherogenesis of vein grafts was assessed in autologous cephalic veins grafted into femoral arteries of 16 normolipemic and 11 hyperlipemic stumptailed macaque monkeys. Before grafting, one half of each vein was distended at high pressure (700 mm Hg) and the other half at low pressure (350 mm Hg). Eight normolipemic monkeys were treated with aspirin, 80 mg/day, and dipyridamole, 50 mg/day, and eight were controls. When grafts were harvested at 12 weeks, tissue cholesterol and,8‐apoprotein content in grafts from untreated monkeys were significantly higher than in ungrafted, uninjured veins. Antiplatelet therapy eliminated the increase in lipid content of vein segments distended at low pressure, and significantly lowered lipid content of segments distended at high pressure, though not to the control levels of ungrafted veins. Seven of the 11 hyperlipemic monkeys received antiplatelet drugs and four did not. The lipid content of all graft segments was significantly higher than in grafted or ungrafted veins from normolipemic monkeys. Antiplatelet therapy again significantly reduced the lipid content in vein segments distended at both levels of pressure, and also reduced the elevated cholesterol content in ungrafted veins. Although this animal preparation differs in many ways from human coronary bypass operations, these observations may be pertinent to the prevention of atherosclerosis in human vein bypass grafts.

Vasodilator effects of the sodium acetate in pooled protein fraction.

Paradoxical hypotension during rapid infusion of plasma protein fraction (PPF) has been attributed to yasodilation by bradykinin in PPF. This study employed a canine, controlled right heart bypass preparation to assess changes in systemic vascular resistance and venous capacitance during infusion of PPF and other possibly vasoactive mediators. Plasma protein fraction caused consistent vasodilation, whereas purified human albumin did not. This vasodilation could be ascribed entirely to acetate, present in PPF as a buffer. Bradykinin in PPF had no effect during venous infusion. Acetate is used widely as a buffer in intravenous and dialysate solutions. Its vasoactive properties must be recognized when such solutions are administered to patients with limited capacity to compensate for sudden vasodilation.

Reactivity of human saphenous veins at arterial perfusion pressures

Vasospasm of human saphenous vein grafts has been reported after aorta-coronary bypass operations. However, it is unknown whether veno-arterial grafts are inherently responsive to vasoconstrictor stimuli after implantation into the arterial circulation or whether their vasomotion is secondary to hemodynamic changes. Thus in this study we used in vitro methods to directly evaluate whether isolated human saphenous vein segments respond to vasoconstrictor agents at arterial pressure levels. External diameter and intraluminal flow were monitored in 12 human saphenous vein segments, which were perfused at 30 ml/min with physiologic salt solution at 90, 70, and 50 mm Hg. Increasing intraluminal pressure higher than 50 mm Hg or exposing the vein to Ca(2+)-free media did not increase vessel external diameter or intraluminal flow, which suggests that human saphenous veins were fully distended at pressures of 50 mm Hg or greater. However, all human saphenous veins were activated by a 1 mumol/L dose of norepinephrine at 50 mm Hg and dilated during subsequent intraluminal infusion of a 1 mumol/L dose of acetylcholine, showing intact vascular smooth muscle and endothelial cell function. In the same vessels, a 1 mumol/L concentration of 5-hydroxytryptamine constricted human saphenous veins by 19%, 22%, and 26% at intraluminal pressures of 90, 70, and 50 mm Hg, respectively, and reduced vessel flow by 6%, 24%, and 42% at the same pressure levels. Similarly, a 1 mumol/L concentration of norepinephrine constricted vessels pressurized at 90, 70, and 50 mm Hg by 9%, 12%, and 17%, respectively, and attenuated vessel flow by as much as 32%. We conclude that human saphenous vein segments are fully distended at perfusion pressures greater than 50 mm Hg, but can dynamically constrict to vasoactive agonists and regulate graft flow at intraluminal pressures as high as 90 mm Hg. Our findings in isolated human saphenous vein segments lend support to clinical observations that human saphenous vein grafts should be regarded as vasoactive conduits after implantation at arterial pressure levels.

Vascular Effects of Spinal Cord Stimulation in the Monkey

Because of clinical reports suggesting beneficial effects of electrical stimulation in peripheral vascular disease, studies have been conducted in the monkey. Regional blood flow was measured prior to, during and following the application of electrical currents to the spinal cord. The flow measurements were made using radioactive microspheres. In addition, tissue temperatures and venous and arterial concentrations of epinephrine and norepinephrine were measured. The results show that electrical stimulation increases blood flow to the skin and muscle. It is hypothesized that the effect is due to sympathetic inactivation secondary to the application of electrical currents.

Comparison of Peak and Modal Aortic Blood Flow Velocities With Invasive Measures of Left Ventricular Performance

The purpose of this study was to determine the accuracy of Doppler-derived modal and maximum velocity and peak and mean acceleration of ascending aortic blood for the assessment of left ventricular systolic function. Studies were performed in six anesthetized open-chest dogs. Doppler-derived modal velocity, maximum velocity, and peak and mean acceleration were compared with left ventricular dP/dt, maximum aortic blood flow, and rate of blood flow measured with an electromagnetic flow probe under varying inotropic states. Maximum Doppler velocity showed better correlation (r = 0.94, y = 0.34 + 3.95) with maximum aortic blood flow than the modal velocity (r = 0.85, y = 1.49 + 3.85x). Peak acceleration also correlated better with the rate of blood flow (r = 0.92, y = 12.3 + 4.92x) than the mean acceleration (r = 0.83, y = 12.2 + 4.27x). Modal and maximum velocity and mean and peak acceleration correlated well with left ventricular dP/dt. We conclude that peak modal and peak maximum velocity and peak and mean acceleration are accurate measurements of left ventricular function. Maximum velocity and peak acceleration are more accurate than modal velocity and mean acceleration.

Comparison of saphenous vein graft relaxation between Plasma-Lyte solution and normal saline solution

Venospasm of saphenous vein grafts may damage endothelial cells and compromise early and late graft performance. Hence it is desirable to identify and use storage solutions that minimize vascular spasm during vein preparation. In view of this, we initiated isometric tension-recording studies in isolated canine and human saphenous vein to evaluate the acute, vasoactive effects of two storage solutions, Plasma-Lyte solution and normal saline solution. In initial experiments, canine saphenous veins were mounted in tissue baths containing physiologic salt solution and tonically constricted by 2 x 10(-6) mol/L norepinephrine. The physiologic salt solution in the bath was then replaced by Plasma-Lyte solution or normal saline solution containing the same norepinephrine concentration, and changes in contraction amplitude were recorded for 90 minutes. Storage in Plasma-Lyte solution at 37 degrees C completely relaxed norepinephrine-activated canine saphenous vein within 20 minutes, whereas veins remained partially constricted in normal saline solution. Both Plasma-Lyte solution and normal saline solution relaxed canine saphenous vein less at room temperature (25 degrees C) than at 37 degrees C, implying that warming of storage solutions in the operating room may promote graft dilation. To identify the mechanism by which Plasma-Lyte solution induced relaxation, we replaced its putative vasodilator components of gluconate and acetate with NaCl, but this alteration did not reduce relaxation induced by Plasma-Lyte solution. However, adding 1.6 mmol/L CaCl2 to Plasma-Lyte solution completely reversed the venodilation, suggesting that the low Ca2+ content of Plasma-Lyte solution confers its relaxant action. Finally, we tested the vasoactive effect of Plasma-Lyte solution on human saphenous vein obtained by discard from coronary bypass operations. Plasma-Lyte solution at 37 degrees C effectively dilated norepinephrine-activated human saphenous vein, inducing complete relaxation within 20 minutes. On this basis, we recommend the use of Plasma-Lyte solution as a venodilating storage solution during coronary bypass operations to optimize vein graft relaxation before implantation.

Effects of Storage Solutions on Contraction and Relaxation of Isolated Saphenous Veins

Summary: Saphenous veins are placed frequently in storage solutions before use as coronary bypass grafts. Controversy remains regarding which solution is optimal for the preservation of endothelium and vascular smooth muscle viability. Thus, this study measured the effect of four different storage solutions on saphenous vein smooth muscle and endothelial cell function. Saphenous vein segments from five baboons were stored for 3 h in one of four storage solutions consisting of physiological salt solution (PSS), University of Wisconsin solution (UWS), normal saline solution (NSS), or autologous whole blood (WB). Following storage, veins were suspended for isometric tension recording in tissue baths filled with PSS. Veins stored in PSS, UWS, and NSS showed similar contractile amplitude and agonist sensitivity to norepinephrine (10−8‐10−4 M) and KCl (20‐100 mM). However, veins stored in WB contracted 31% less to KCl on average than those stored in the other three solutions (p < 0.05). The direct vascular muscle vasodilator, papaverine (10−7‐10−4 M), and the endothelium‐dependent dilator, A23187 (10−5 M), relaxed all vein preparations equally well. These results suggest that after storage in PSS, UWS, and NSS, contractile and relaxant vascular responses are similar in isolated saphenous veins. However, although veins stored in WB show comparable relaxation responses, they demonstrate an impaired vascular contraction immediately after storage. We conclude that storage of veins in blood may immediately modify vascular smooth muscle function.

Aspirin or dipyridamole individually prevent lipid accumulation in primate vein bypass grafts

Although platelet inhibition with both aspirin and dipyridamole is widely prescribed for patients with coronary artery bypass grafts, data are lacking to prove that combined drug therapy has greater efficacy in preserving graft integrity than either drug given independently. Thus, the ability of combined vs single drug therapy to reduce cholesterol and apolipoprotein-B accumulation were compared in autologous cephalic veins grafted into femoral arteries of 23 stump-tailed macaque monkeys. Ten monkeys were studied in 2 phases. They were treated with aspirin (80 mg/day) during 1 phase and with dipyridamole (50 mg/day) during the other phase. Five monkeys received aspirin plus dipyridamole in combination and 8 received no medication and served as controls. When grafts were removed 3 months after insertion cholesterol and apolipoprotein-B concentrations in grafts were similar for groups treated with aspirin, with dipyridamole, and with the drugs combined, and in each of the treated groups these concentrations were significantly reduced compared with grafts from untreated control monkeys. Cholesterol and apolipoprotein-B concentrations in grafts from the treated groups were similar to concentrations in normal ungrafted veins, whereas cholesterol and apolipoprotein-B levels in grafts from control monkeys were significantly greater than those in ungrafted veins (250% and 925% of normal, respectively). Our findings reaffirm the ameliorative effect of anti-platelet drugs in reducing the accumulation of lipid in vein bypass grafts and indicate that the efficacy of aspirin or dipyridamole given individually equals that of the combination of these drugs in this subhuman primate model. The relation of the lipid-lowering effect of these agents to their antithrombotic effect is uncertain.

Both Dietary Fish-Oil Supplementation and Aspirin Fail to Inhibit Atherosclerosis in Long-term Vein Bypass Grafts in Moderately Hypercholesterolemic Nonhuman Primates

BACKGROUND Aortocoronary vein bypass grafts are vulnerable to late atherosclerotic occlusion. Conventional platelet inhibitor therapy provides early but not persistent protection against graft failure. Evidence suggests that consumption of marine foods may reduce cardiovascular disease, possibly because of the unique long-chain unsaturated omega-3 fatty acids present in these foods. We hypothesized that dietary fish-oil supplementation would protect against atherosclerosis in vein bypass grafts. METHODS AND RESULTS Thirty-three moderately hypercholesterolemic cynomolgus macaques were divided into four groups: control, control+aspirin, fish oil, and fish oil+aspirin. Each control group received olive oil as placebo to equalize calorie and fat consumption with that of the fish-oil groups. Both oils were in ethyl ester form, with the fish oil providing 0.88 g/d eicosapentaenoic acid. The aspirin dose was 40 mg/d. Cephalic vein grafts were interposed bilaterally in the carotid arteries and excised for analysis at 4 years. Bleeding time was significantly prolonged in all groups receiving fish oil or aspirin (P<.05). Plasma cholesterol levels were similar among groups, averaging 6.9+/-2.4 mmol/L (267+/-94 mg/dL). The extent of atherosclerosis in vein grafts did not differ among groups as evaluated both by Sudan IV staining of intimal lipid lesions (27+/-21% of total surface area, P=.89) and analysis of cholesterol content (236+/-203 nmol/mg, 9.1+/-7.8 microg/mg, P=.85). Vein graft connective tissue composition was also unaffected by treatment. CONCLUSIONS Our findings do not support the use of concentrated dietary fish-oil supplements or aspirin for the prevention of atherosclerosis in long-term vein bypass grafts. Consumption of fish flesh or less refined oil preparations could have effects different from those of the purified fish-oil ethyl esters we used.

Hemodynamic and hormonal abnormalities in canine aortic coarctation at rest and during exercise

This study was designed to determine the hemodynamic and hormonal consequences of aortic coarctation at rest and during treadmill exercise. Twelve normal adult dogs served as controls. In eight dogs coarctation was created within 1 week of birth by banding the aorta just proximal to the ductus ligament, thereby fixing luminal diameter at 1 to 2 mm. Studies were performed 18 months after operation. Vascular pressures were monitored proximal and distal to the coarctation, cardiac output and regional blood flow were evaluated with radioactive microspheres and blood samples were collected for determination of hormone levels and blood gases. At rest, systolic pressure in the proximal aorta was 130 +/- 12 mm Hg (mean +/- SD) in the control group and 167 +/- 16 mm Hg in dogs with coarctation (p less than 0.01). During exercise at a level that doubled heart rate and cardiac index, mean aortic pressure increased by 11 and 31% (p less than 0.01) in the control and the coarctation group, respectively. Mean distal aortic pressure increased by 8% during exercise in control dogs but decreased by 29% in dogs with coarctation. Exercise decreased flow to the kidneys and the large intestine in the coarctation group. Plasma norepinephrine concentrations were greater in the coarctation group than in control dogs at rest; during exercise, plasma norepinephrine, epinephrine and renin activity increased in both groups, but to a greater degree in the group with coarctation. These results confirm an abnormality in renal and gut perfusion in experimental coarctation and suggest that this may be related to a decline in perfusion pressure.(ABSTRACT TRUNCATED AT 250 WORDS)