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European Heart Journal 1990 11(Supplement E):41-52; doi:10.1093/eurheartj/11.suppl_E.41
Copyright © 1990 by the European Society of Cardiology.
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© 1990 The European Society of Cardiology

Pathobiology of human familial hypercholesterolaemia and a related animal model, the Watanabe heritable hyperlipidaemic rabbit

L. M. Buja*,, F. J. Clubb{ddagger}, D. W. Bilheimer|| and J. T. Willerson{dagger}

* Department of Pathology, The University of Texas Health Science Center at Houston U.S.A.
{ddagger} Department of Internal Medicine, The University of Texas Health Science Center at Houston U.S.A.
|| Department of Pathology, The University of Texas Southwestern Medical Center at Dallas U.S.A.
{dagger} Department of Internal Medicine, The University of Texas Southwestern Medical Center at Dallas U.S.A.

Address for reprints: L. Maximilian Buja. M.D., Professor and Chairman, Department of Pathology and Laboratory Medicine, The University of Texas Health Science Center at Houston, 6431 Fannin St., MSMB 2.136, Houston, Texas 77030, U.S.A.

Defective expression of low density lipoprotein (LDL) receptors is the basic genetic defect in human familial hypercholesterolaemia (FH) and its animal counterpart, the Watanabe heritable hyperlipidaemic (WHHL) rabbit. The pathologic manifestations of human FH were evaluated based on the study of material from six subjects with homozygous FH and a review of the literature. This analysis indicated that homozygous FH is characterized by accelerated atherosclerosis and prominent lipid accumulation in macrophages and other stromal cells of the aortic and mitral valves, skin, tendon, and, variably, in other extravascular sites. Disease progression was studied in the WHHL rabbit. From birth to 1 year, WHHL rabbits show evidence of progressive disease of the aorta with accumulation of birefringent lipid in intimal lesions, including fatty streaks, raised foam cell lesions, and plaques (atheromas), as well as in the media. At 1–2 years, WHHL rabbits develop coronary atherosclerosis and focal extravascular lipid deposits, including subcutaneous and tendinous xanthomas. Vascular lesion development is associated with adhesion of monocytes and other leucocytes to the endothelium. The cells of the intimal lesions are lipid-containing macrophages, smooth muscle cells and foam cells. Most of the intracellular lipid is in the form of non-membrane-bound neutral lipid droplets indicating that the cytoplasm is the major site of lipid storage. Similar ultrastructural features are shown by human FH lesions. Observations are reviewed regarding therapeutic approaches aimed at altering the pathologic expression of familial hypercholesterolaemia, including the negative results of treatment of WHHL rabbits with the calcium-channel antagonist, verapamil, and omega-3 fatty acids.

Key Words: Familial hypercholesterolaemia • pathology • Watanabe heritable hyperlipidaemic (WHHL) rabbit • verapamil • omega-3 fatty acids


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