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SUMMARY 1. Atherosclerotic lesions can be made to develop or regress in the albino rat by treatments that, respectively, elevate or depress the serum cholesterol concentration. 2. After young rats had been given a new diet for 45–72 days, the degree of atherosclerosis attained was related to the new serum cholesterol level and was independent of the previous degree and severity of atherosclerosis. 3. Regression of lesions established for about 1 month occurred if the serum cholesterol level was lowered, either by changes in the diet or by administering 3:5-diiodo-d-thyronine (DT2). The relation between serum cholesterol level and Sudan score (see p. 70) appeared to be independent of the method used for lowering the serum cholesterol level. 4. Regression of lesions established for about 6 months occurred if the serum cholesterol level was lowered either by changes in the diet or by administering DT2, but the rate of regression was slower than when the lesions had been present for a short time only. 5. When the serum cholesterol levels of rats given an atherogenic diet for 6 months had been reduced to normal values by feeding stock diet, the rats still had a high degree of atherosclerosis. When stock diet containing DT2 was then fed, there was no increase in the rate of regression of lesions over that obtained on the stock diet alone. 6. Dietary administration of different amounts of 3:5-diiodo-4(4′-hydroxy phenoxy) phenyl acetic acid (DIAC) or DT2 to groups of rats maintained on a diet containing cholesterol and cholic acid over a 9-month period resulted in a reduction of serum cholesterol levels to an extent roughly related to the dose of drug given. Liver cholesterol levels were also reduced in the older animals. Arterial atheroma was reduced by both compounds to an extent proportional to the dose administered. Both compounds, at all dose levels, increased the rate of growth of animals compared with that of controls. Both compounds depressed liver weights at all dose levels and increased the weight of the pancreas at the higher dose levels, if these weights were expressed per 100 g/body weight.

SUMMARY 1. Methods are described for comparing the activity of compounds related to thyroxine in controlling the increases in cholesterol concentration in the serum and in the liver, and the increased sudanophilia in the cardiovascular system, after feeding diets containing cholesterol, choline, fat and cholic acid. 2. The three test procedures described placed the compounds tested in a similar order of activity. Little activity could be detected in compounds not containing an iodine atom at both the 3 and 5 positions in the molecule. Compounds with iodine atoms at the 3:5:3′ positions were more active than those substituted at the 3:5:3′:5′ positions, which in turn were more active than the 3:5 di-substituted compounds. The l isomers of 3:5:3′-triiodo-thyronine and thyroxine were more active than the d isomers, but 3:5-diiodo-d-thyronine was as active as 3:5-diiodo-l-thyronine. 3. Methods are also described for comparing the activity of the same compounds in causing ventricular enlargement in mice maintained on a stock diet and in rats maintained on a diet containing added fat, cholesterol, choline and cholic acid or on a stock diet with added thiouracil. 4. The tests involving ventricular hypertrophy placed all the compounds tested in approximately the same order of activity, broadly similar to that shown in published results obtained by the oxygen consumption rate or antigoitrogenic tests. Little, if any, activity could be detected except in compounds with iodine atoms at both the 3 and 5 positions in the molecule. Compounds with iodine atoms at the 3:5:3′ positions were more active than the corresponding compounds with iodine atoms at the 3:5:3′:5′ positions, which in turn were more active than the 3:5 di-substituted products. Iodinated l-thyronine derivatives were more active than the corresponding thyroacetic acid compounds, which in turn were more active than the thyroformic acid derivatives. Iodinated l-thyronine derivatives were more active than the d-isomers. 5. The ratio of the activity of a compound in preventing elevation of serum cholesterol to its effect on the heart was about three times as great for some, such as 3:5-diiodo-d-thyronine and d-thyroxine, as for others, such as 3:5:3′-triiodo-l-thyronine and l-thyroxine.