Hyperplasia In Experimental Vein Grafts Research Articles

Reduction of vein graft intimal hyperplasia by ex vivo treatment with desferrioxamine manganese.

Reversed vein grafting exposes the venous tissue to a period of ischemia, reperfusion and subsequent free radical generation which may contribute to endothelial injury and/or damage, smooth muscle cell proliferation and the later development of intimal hyperplasia. The effects of ex vivo treatment with desferrioxamine Mn+3 (DFMn), a cell-permeable free radical scavenger, on the development of intimal hyperplasia in experimental vein grafts was examined. Twenty New Zealand white rabbits received a reversed vein interposition bypass graft into the ipsilateral common carotid artery. Ten explanted veins were immersed in a heparinized (5 IU/ml) saline solution, and 10 others were immersed in a similar solution containing DFMn (1 mM) for 45 min prior to reimplantation. There were no short-term functional or morphologic toxic side effects associated with DFMn treatment on either the endothelial or smooth muscle cells of the veins. At 28 days, grafts (n = 20) were perfusion-fixed in vivo for histological and morphometric studies. There was a significant reduction in intimal thickening in the DFMn-treated group compared to the untreated group. The thicknesses of the intimal hyperplasia in the proximal segments were 50.6 +/- 6.3 vs. 76.9 +/- 3.2 microns (p < 0.05), in the middle segments 42.0 +/- 5.0 vs. 84.3 +/- 5.4 microns (p < 0.05) and in the distal segments 55.7 +/- 5.0 vs. 88.3 +/- 6.2 microns (p < 0.05) for treated and untreated animals, respectively. No evidence of long-term toxicity was found.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic ACE Inhibition Reduces Intimal Hyperplasia in Experimental Vein Grafts

Intimal hyperplasia is an important factor in the pathophysiology of vein graft failure. Local renin-angiotensin systems recently have been shown to modulate the development of intimal hyperplasia in arteries after intimal injury. The effect of chronic angiotensin-converting enzyme (ACE) inhibition on the development of intimal hyperplasia in experimental vein grafts was examined in this study. Ten New Zealand White rabbits received 10 mg/kg of captopril daily in their drinking water. One week later the right carotid artery was divided and bypassed with the reversed right external jugular vein in these rabbits and in 10 matched controls. Captopril was continued for 28 days after operation, when all the grafts were harvested. Five grafts from each group were perfusion fixed, and the intimal thickness in the proximal, middle, and distal segments was determined. Rings from the remaining grafts (n = 20 in each group) were studied in vitro under isometric tension, and their responses to norepinephrine (NE), histamine (HIST), serotonin (5-HT), angiotensin I (AI), and angiotensin II (AII) was measured. The intimal thickness of the proximal, middle, and distal segments of the captopril-treated grafts were significantly less than controls, being reduced in all segments by approximately 40% (p less than 0.0001). With regard to vasoreactivity, the captopril-treated grafts were hypersensitive to 5-HT (control ED50 5.5 +/- 0.5 X 10(-7) mol/L vs. captopril-treated 1.1 +/- 0.2 X 10(-6) mol/L; p less than 0.005) although the maximal response was significantly reduced (control 1.6 +/- 0.3 g vs. captopril-treated 0.8 +/- 0.1 g; p less than 0.05). There were no differences in sensitivity between control and captopril-treated rings with respect to NE, HIST, AI, or AII. Four of the ten captopril-treated segments, however, failed to respond to AI, and the maximal active tension of the responders was significantly reduced (control 0.47 +/- 0.06 g vs. 0.20 +/- 0.05 g; p less than 0.02). These results suggest that ACE is involved in the modulation of vein graft intimal hyperplasia, and that ACE inhibitors may have therapeutic applications in patients undergoing vein bypass procedures.

Reduction of Intimal Hyperplasia and Enhanced Reactivity of Experimental Vein Bypass Grafts with Verapamil Treatment

Recent studies have shown that calcium antagonists exert an antiatherogenic effect in animals fed cholesterol. Vein graft intimal hyperplasia is believed to be an early event in atherosclerotic lesion formation, which is a significant cause of graft failure. Altered vasoreactivity has also been postulated in the etiology of vein graft failure. Therefore this study examined the effect of verapamil treatment on the development of intimal hyperplasia and the vasoreactivity of experimental vein bypass grafts. The right external jugular vein was grafted into the right carotid artery of 30 male New Zealand white rabbits fed normal rabbit chow. The left external jugular vein was used as the control vein. Fifteen animals received verapamil (1.25 mg/day for 28 days) via the femoral vein by means of an osmotic pump. In 15 control animals the pump contained saline. Plasma verapamil concentration was 50.9 +/- 13.2 ng/mL (x +/- SEM), a dose that showed no effect on either blood pressure, total serum cholesterol, or in vitro platelet aggregation to ADP. Fourteen of fifteen grafts were patent in each group, for a patency rate of 93%. Histologic examination using computer morphometry showed significant reduction of intimal hyperplasia at the proximal, middle, and distal graft segments (p less than 0.05). In addition in vitro isometric tension studies of the vein grafts and control veins showed that verapamil causes enhanced reactivity of both vein grafts and control veins in response to norepinephrine and histamine (p less than 0.05). Reactivity of vein grafts to serotonin was unaltered. While none of the normal veins in the control group responded to serotonin, normal veins treated with verapamil contracted readily in response to serotonin. Endothelial-dependent relaxation to acetylcholine was absent in both control and verapamil-treated vein grafts, while normal veins from both groups responded to the same extent to acetylcholine. Because we could not demonstrate any difference in platelet or endothelium function between untreated and verapamil-treated animals, we examined the direct effect of verapamil on smooth muscle. Verapamil significantly inhibited [3H]-thymidine incorporation into DNA in vascular smooth muscle cells in culture in a dose-dependent manner. Verapamil treatment significantly reduces intimal hyperplasia in experimental vein grafts and inhibits smooth muscle cell proliferation in culture. Furthermore the enhanced reactivity to norepinephrine and histamine in the verapamil-treated vessels has no detrimental effect on the patency rate at 4 weeks. Thus by inhibiting intimal hyperplasia, calcium antagonists may improve the long-term patency of vein bypass grafts.