THE PATHOGENESIS OF ATHEROSCLEROSIS - A CRITICAL-EVALUATION OF THE EVIDENCE

The consistent topography, transmural involvement, and variation in se verity and rate of progression in individual atherosclerotic lesions c ollectively indicate the dominant, primary role of hemodynamics. Speci fic anatomic configurations, vessels with elevated pressure, high velo city, or disturbed flow and iatrogenic production of accelerated ather osclerosis and its complications in therapeutic venous bypass grafts a nd arteriovenous shunts point to this role. The morphology and complic ations are consistent with the loss of cohesion and tensile strength o f mural constituents and irreconcilably different from those of choles terol- or fat-overfed animals and from other metabolic lipid storage d isorders. These observations preclude dietary and circulating humoral factors and negate currently prevailing etiologic hypotheses that do n ot account for topography, pathogenesis, or complications. Atheroscler osis is the response to hemodynamically induced repetitive tensile str esses due to the pulse pressure and lesser flow-generated vibrations r esulting in bioengineering fatigue occasioned by cumulative molecular fragmentation of mural constituents. This phenomenon also accounts for free-radical formation and lipoperoxidation. Atherosclerosis thus con stitutes the combined manifestations of tissue fatigue and compensator y repair. When fatigue predominates, mural failure leads to the develo pment of the primary complications (mural tears, dissection, ectasia, tortuosity, aneurysms). Lipid accumulation and thromboembolism are sec ondary phenomena. Fatigue onset is enhanced by hypertension and acquir ed or inherited defects of individual mural constituents. Iatrogenic a nd experimental production of atherosclerosis, its pathogenesis, and c omplications by hemodynamic means provides the ultimate proof of the c ausal role of bioengineering fatigue. (C) 1997 by Elsevier Science Inc .