Mechanical factors in restenosis; hemodynamic studies in humans

MECHANICAL FACTORS IN RESTENOSIS; HEMODYNAMIC STUDIES IN HUMANS PeterJEHM Kitslaar, Leo Ho&a, Jan Hh4 Tordoir, Arnold PG Ho&s, Mat JAP Daemen CardiovascularResearchInstitute (CARIM),University of Llmburg, Maastricht,The NETHERLANDS Mechanicalforcesexerted on the vessel wal, in particular on the endothelialcells, are consideredimportant stimuli for the developmentof intimal hyperplasia causingrestenosisin the fast year after PTA or stentingof arteries,prosthetic or venous bypass grafting in the arterial system or the constructionof AV tistulas for hemodialysis.Endotheliai cells undergo frictional drag (shear)by the bloodstreamand mechanical stretching due to vesselwall distension.Both may be abnormal in arteries and veins with a modifmd geometrydue to vascular interventions causingperi-anastomoticmismatchin elastic propertiesor local abnormalities in shearrate. Recentlynon-invasive studiesof local vesselwall kinetics and flow characteristicsin the humanvasculaturebecamepossible with the combineduseof an ultrasoundVessel Wall Doppler Tracking (VWDT) system- measuringvessel diameter (D) and distension(AD) during a numberof heartbeats- and an echo-Doppler systemfor measurementof IocaI PeakSystolic Velocity (PSV) of the bloodstream.From D, AD and PSVthe Relative Distension(RD= AD/D)as measureof elastic property of the vessel and the normalizedPSV (= PSV/D) as approximation of local Peak ShearRate (PSR)can be computed. In a seriesof prospective clinical studies initial (post-construction)peri-anastomicelastic properties and PSR’s in venous femorodistal bypassgrafts (n =43) and prosthetic high flow AV hemodialysististulas (n=24) were correlatedwith the occurrenceof&noses during follow up. Furthermore,correlations betweencellular proliferation patterns,luminal endothelial cell coverageand initialand late PSR’swere determinedin 35 human stenotic lesions,surgically harvestedfrom thesebypassgrafts and AV-tistulas. Thesestudiesshowedthat an initial peri-anastomotlcmismatchin elastic propertiesdoesnot play a major role in the occurrenceof stenosesin AV tistulas and peripheral bypasses. A correlation was found between initial high PSR’s and the later deveiopmentof stenoses,found mainty near the proximal anastomosesof the (reversed)venousbypassgrafts and at the venous side of the AV tistulas. The data from the histologic study suggestenhancedcellular proliferation in the stenoticsegmentsin comparison to the nonstenoticadjacentsegments.In the stenosesa positive correlation was found betweenthe endothelial cell coverage of the hnnenand the subendothelialcellular proliferation. The degreeof proliferation was negatively correlatedwith the magnitude of the PSR, measured2 weeks before harvesting the stenoses. Thesefindings suggestthat high shearratesmay have a stimulating effect on the developmentof stenosingintimal hyperplasia, but, oncethe stenoseshave developed, may have an inhibiting effect on the cellular proliferation in the stenoses,through endothelial denudation.

Agents which suppress smooth muscle proliferation or migration in culture or in experimental injury models have failed to reduce the incidance of raa+rsnrcris f01Lowing angioplastg or atherectomy or of obstructions at aneotamoses foiloww revm+L~isetion Recent findiugs sugpat that non-atherosclerotic intistel thitik@f~ are procedures. reflections of rpodeling reections which tend to restore xofllal levels of wall @W&t end Uhen flow conditions following interventiona psevext the rare*tiLil~nt of tensile stress. deformities or baseline wall shear stress levels of about 15 dynes/em 2, due to irreducible persistent lov flow states, the proliferative reaction, If barali2te conditians restenosis supervenes. differentiates into a media-like structure, persistence of a pateat lumen. We tested the sf We reduced shear stress to helf the euntxoL v&m by lfgetion iliac anastcaeoses in rabbits. which tasulted in a 4 f*Xd tmr%we of the internal iliac and superficial femoral arteries, in intixal thihiokening and i 2 fold increase in lmen area stenosis (p*ia.OI vs coW.rol~). Pe also assessed the quantitative relationship between well shesr stresses and- intimal !&ear thickenings about experimuntel end to side pxostheois (I%@) to artery ax.WW$%S. stress, detsneined at 24 axial locations in an axurate upscale silicone model reveeled a significant'inverse correletion between inti@a1 thi&ux%~& in the gxalgts et& wslL s&att in fbstule vas estabLi$'Wd, shear SWess the model (ri0.6, p