DEVELOPMENT AND PROGRESSION OF ATHEROSCLEROSIS IN AORTA FROM HETEROZYGOUS AND HOMOZYGOUS WHHL RABBITS - EFFECTS OF SIMVASTATIN TREATMENT

This study was conducted to define progression of atherosclerosis in b oth homozygous and heterozygous Watanabe heritable hyperlipidemic (WHH L) rabbits and to investigate the ability of the HMG CoA reductase inh ibitor simvastatin to attenuate progression of the disease. We examine d contractile responses to phenylephrine and endothelium-dependent rel axation in response to carbachol in thoracic aorta at 3, 6, 9, and 12 months in control New Zealand White (NZW) rabbits, homozygous WHHL rab bits, and heterozygous WHHL rabbits. Homozygous and heterozygous rabbi ts were treated with simvastatin (10 mg/kg per day) from 3 to 6 months and from 9 to 12 months of age. Simvastatin significantly reduced ser um cholesterol levels in young heterozygotes, with a nonsignificant tr end toward a reduction in older heterozygotes. In homozygotes, no sign ificant fall was observed. Contractile function declined progressively with age in all groups-most in homozygotes and least in NZW rabbits. Relaxation was unaffected by age in NZW rabbits; relaxation declined i n the heterozygotes and declined to a greater extent in homozygotes. S imvastatin retarded the loss of function in the young heterozygotes. S imilar trends were observed in young homozygotes and older heterozygot es, with no effect in older homozygotes. Histological studies revealed the progressive development of early atherosclerosis in heterozygotes , and more advanced atherosclerosis was observed in homozygotes. Simva statin did not inhibit development of atheroma. A correlation was obse rved between vascular function and structure. However, functional chan ges preceded the development of atheroma. In addition, we have demonst rated that simvastatin can help to reduce the loss of vascular functio n associated with the progression of atherosclerosis in the heterozygo us WHHL rabbit.