Partial Ileal Bypass Research Articles

Reduction of LDL production rate in ileal bypassed rabbits treated with lovastatin

The effect of lovastatin on the low density lipoprotein metabolism in bypassed rabbits was investigated. Partial ileal bypass effectively reduced total and low density lipoprotein (LDL) cholesterol by 44 and 48% respectively. The LDL drop was due to an increased fractional catabolic rate (FCR) of apolipoprotein B (apo B) from 0.74 to 1.27 pools per day with no effect on the apo B absolute catabolic rate and an increased expression of liver LDL receptors (+71%). Association of lovastatin with PIB resulted in a further decrease of total and LDL cholesterol (56 and 75% respectively) as compared to bypassed animals, without effects on the LDL FCR (1.27 +/- 0.11 versus 1.42 +/- 0.13 pools/day) or the expression of LDL receptors by the liver. The reduction of LDL was due to a decrease of the apolipoprotein B absolute synthetic rate (8.5 +/- 1.7 versus 13.6 +/- 1.7 mg/day). From these data we conclude that in bypassed rabbits lovastatin lowers total and LDL cholesterol mainly by reducing apolipoprotein B production rate.

Partial ileal bypass reduced coronary artery disease morbidity and cholesterol levels after myocardial infarction

Source Citation Buchwald H, Varco RL, Matts JP, et al., and the POSCH Group. Effect of partial ileal bypass surgery on mortality and morbidity from coronary heart disease in patients with hypercholesterolemia. Report of the Program on the Surgical Control of the Hyperlipidemias (POSCH). N Engl J Med. 1990;323:946-55.

Effect of Partial Ileal Bypass Surgery on Mortality and Morbidity from Coronary Heart Disease in Patients with Hypercholesterolemia

The Program on the Surgical Control of the Hyperlipidemias (POSCH), a randomized clinical trial, was designed to test whether cholesterol lowering induced by the partial ileal bypass operation would favorably affect overall mortality or mortality due to coronary heart disease. The study population consisted of 838 patients (417 in the control group and 421 in the surgery group), both men (90.7 percent) and women, with an average age of 51 years, who had survived a first myocardial infarction. The mean follow-up period was 9.7 years. When compared with the control group at five years, the surgery group had a total plasma cholesterol level 23.3 percent lower (4.71 +/- 0.91 vs. 6.14 +/- 0.89 mmol per liter [mean +/- SD]; P less than 0.0001), a low-density lipoprotein cholesterol level 37.7 percent lower (2.68 +/- 0.78 vs. 4.30 +/- 0.89 mmol per liter; P less than 0.0001), and a high-density lipoprotein cholesterol level 4.3 percent higher (1.08 +/- 0.26 vs. 1.04 +/- 0.25 mmol per liter; P = 0.02). Overall mortality and mortality due to coronary heart disease were reduced, but not significantly so (deaths overall [control vs. surgery], 62 vs. 49, P = 0.164; deaths due to coronary disease, 44 vs. 32, P = 0.113). The overall mortality in the surgery subgroup with an ejection fraction greater than or equal to 50 percent was 36 percent lower (control vs. surgery, 39 vs. 24; P = 0.021). The value for two end points combined--death due to coronary heart disease and confirmed nonfatal myocardial infarction--was 35 percent lower in the surgery group (125 vs. 82 events; P less than 0.001). During follow-up, 137 control-group and 52 surgery-group patients underwent coronary-artery bypass grafting (P less than 0.0001). A comparison of base-line coronary arteriograms with those obtained at 3, 5, 7, and 10 years consistently showed less disease progression in the surgery group (P less than 0.001). The most common side effect of partial ileal bypass was diarrhea; others included occasional kidney stones, gallstones, and intestinal obstruction. Partial ileal bypass produces sustained improvement in the blood lipid patterns of patients who have had a myocardial infarction and reduces their subsequent morbidity due to coronary heart disease. The role of this procedure in the management of hypercholesterolemia remains to be determined. These results provide strong evidence supporting the beneficial effects of lipid modification in the reduction of atherosclerosis progression.

Partial Ileal Bypass for Hypercholesterolemia

Between 1963 and 1968, 57 patients underwent partial ileal bypass (PIB) at the University of Minnesota for primary hypercholesterolemia. Preoperative total plasma cholesterol (TC) was 363.3 +/- 136.8 mg/dL (mean +/- SD) in these patients. Baseline and follow-up TC results demonstrated highly significant (p less than or equal to 0.001) TC reduction, 34% (n = 48), 28% (n = 49), 35% (n = 26), 35% (n = 11), and 30% (n = 25) at 1, 2 to 5, 6 to 10, 11 to 15, and more than 20 years, respectively, after PIB. In 21 patients with baseline, 1-year, and more than 20-year results TC decreased 33% by 1 year and remained 29% less than baseline more than 20 years after surgery (p = NS versus 1 year). Plasma triglyceride results were available in fewer patients, and no statistically significant changes developed after PIB. Two patients (3.5%) underwent PIB reversal, one for intractable diarrhea and one for recurrent nephrolithiasis. In the 25 nonreversed, long-term survivors, no statistically significant weight change was noted. Twenty-four per cent had 0 to 2, 52% had 3 to 5, and 24% had more than 5 bowel movements per day. Subsequent cholecystectomy was required in eight patients, and nephrolithiasis developed in 10 (40%). During 20 to 26 years, most survivors developed clinically apparent atherosclerosis: angina (60%), myocardial infarction (16%), or coronary artery bypass (28%). Coronary heart disease was the predominant cause of death among nonsurvivors (80%). Overall survival rates were 95% 88%, 75%, 59%, 53%, and 41% at 1, 5, 10, 15, 20, and 25 years, respectively, after PIB. Partial ileal bypass leads to highly significant TC reduction, which is sustained, essentially unchanged, more than 20 years after operation. In comparison to available epidemiologic and clinical trial data, these results support the hypothesis that TC reduction has a beneficial effect in patients with hypercholesterolemia.

Calcium Absorption and Bone Mineral Content in Patients Subjected to Ileal Bypass because of Familial Hypercholesterolaemia

Calcium absorption and bone mineral content were studied prospectively in 30 patients with familial hypercholesterolaemia subjected to partial ileal bypass surgery. One-third of the patients were followed up for 10 years after the operation. Six months postoperatively calcium absorption decreased significantly, from a median of 16% to 13%. The effect persisted up to 5 years of follow-up study. Ten years after the operation the absorption of calcium (median, 14.5%) was not significantly different from the preoperative calcium absorption (median, 16%). Bone mineral content, measured in 76% of the patients, was retained in all patients studied. A significant correlation was present between calcium absorption and urinary calcium. The reduction in calcium absorption did not correlate with increases in faecal fat. Other long-term side effects were persistent diarrhoea and moderate steatorrhoea. A significant weight loss was slowly regained in most patients. An increase of renal oxalate excretion was only small and transient in most patients. The study shows that bypass of the terminal 200 cm of ileum for familial hypercholesterolaemia causes moderate diarrhoea and steatorrhoea in most patients but only a slight reduction of intestinal calcium absorption and apparently no risk of bone demineralization. A benefit of a postoperative calcium and vitamin D supply cannot be excluded.

Lipid related consequences of intestinal malabsorption.

The small intestine plays a key role in lipid metabolism by absorbing fat and synthesising apoproteins. Fat malabsorption secondary to intestinal disease results in abnormalities of lipoprotein concentration and composition and can lead to deficiency of essential fatty acids and fat-soluble vitamins. Malabsorption of fat can be induced by administration of neomycin and malabsorption of bile acids by administration of anion-exchange resins or by creating a partial ileal bypass. These induced forms of malabsorption are useful in the treatment of hyperlipidaemic patients liable to atherosclerosis.

Low-density lipoprotein catabolism in WHHL rabbits after partial ileal bypass surgery

The effect of partial ileal bypass surgery (PIB) on lipoprotein concentrations and compositions and on the catabolism of low-density lipoproteins (LDL) was studied in Watanabe heritable hyperlipidemic (WHHL) rabbits. After PIB, total serum cholesterol was 65% lower (6.22 +/- 1.58 vs. 17.24 +/- 3.22 mmol/l) and LDL cholesterol 81% lower (2.02 +/- 0.95 vs. 10.90 +/- 3.60 mmol/l) than in control WHHL rabbits; cholesteryl esters, expressed as percentage of mass, were 55% lower in the very-low and intermediate-density lipoprotein (VLDL + IDL) fractions, and 45% lower in LDL, whereas triacylglycerols were 89% higher in VLDL + IDL and 121% higher in LDL. The fractional catabolic rate (FCR) of LDL protein (apoLDL) from operated animals was 10% higher than that from controls in all animals (0.55 +/- 0.10 vs. 0.50 +/- 0.10 pools/day; P less than 0.01). The FCR of autologous apoLDL in PIB rabbits was 50% higher than that of autologous apoLDL in control rabbits (0.63 +/- 0.05 vs. 0.42 +/- 0.06 pools/day); this was not caused by induction of receptor-mediated clearance of LDL. The production rate of apoLDL after PIB in PIB rabbits was 50% lower compared to control apoLDL in controls (26.0 +/- 6.7 vs. 51.7 +/- 16.4 mg/kg per day). We conclude that PIB lowers LDL cholesterol in WHHL rabbits by a decreased production of LDL, by an increased non-specific clearance of LDL and by compositional changes, which lead to LDL particles containing less cholesterol.

Program on the surgical control of the hyperlipidemias (POSCH): Design and methodology

The Program on the Surgical Control of the Hyperlipidemias (POSCH) is a prospective, randomized, controlled, multi-center, secondary, atherosclerosis intervention trial. POSCH addresses the therapeutic arm of the lipid-atherosclerosis theory, i.e. whether lowering of plasma cholesterol is directly related to a reduction in atherosclerosis risk. In this trial, lipid modification is accomplished by the partial ileal bypass operation. Between 1975 and 1983, 838 patients were randomized into this study. All patients were between 30 and 64 years of age, had survived one and only one electrocardiogram and enzyme-documented myocardial infarction; and had a total plasma cholesterol of at least 220 mg/dl or a low density lipoprotein (LDL)-cholesterol of at least 140 mg/dl if the total plasma cholesterol was between 200 and 219 mg/dl after a minimum of 6 weeks of dietary fat and cholesterol restriction. The primary response variable in POSCH is overall mortality. Secondary endpoints include fatal and non-fatal myocardial infarctions, serial electrocardiographic changes, and, most importantly, sequential coronary arteriography changes. The minimum follow-up is currently planned to be 7 years. Study analyses will be made primarily on the “intention to treat” basis. This paper is the first detailed presentation of POSCH design and methodology. Included are descriptions of study design, implementation, and data collection, including data processing, quality assurance/quality surveillance, and patient safety monitoring. POSCH seeks to demonstrate a significant reduction in overall mortality by lipid modification and to validate the use of coronary arteriographic change as a surrogate endpoint for change in coronary heart disease risk.

Risk of brain infarction in familial hypercholesterolemia.

We followed 54 subjects with heterozygous familial hypercholesterolemia for an average of 10 (range 3-14) years. Half were treated surgically with partial ileal bypass and the other half (matched for age, sex, coronary heart disease, blood pressure, diabetes mellitus, smoking, obesity, and serum cholesterol concentration) were treated conservatively with diet and hypolipidemic drugs. The mean decrease in serum cholesterol concentration from the average value of 522 mg/dl on entry into the study was 32% in the surgically treated group and 10% in the conservatively treated group. One quarter of the subjects (14 of 54) had symptomatic cerebrovascular disorders and one tenth (six of 54) suffered a brain infarction at a mean age of 43 (range 30-57) years. Two thirds of the brain infarctions occurred during follow-up. The method of treatment of familial hypercholesterolemia did not affect the number of new cerebrovascular events. The incidence of brain infarction was 7.4/1000/yr. The risk of brain infarction in these subjects with familial hypercholesterolemia was at least 20 times higher than in the general population. We conclude that symptomatic subjects with familial hypercholesterolemia have not only a high risk of coronary heart disease but also a high risk of cerebrovascular disorders.

Effect of partial ileal bypass and lovastatin, alone or in combination, on the expression of LDL receptors in the liver

En la rehabilitación de niños y adolescentes con asma bronquial, a pesar de los buenos tratamientos farmacológicos existentes, se aprecian sobrecargas corporales y anímicas, así como falta de cooperación terapéutica. Los pacientes desean abordajes no puramente farmacológicos y se preguntan sobre los métodos terapéuticos alternativos. Por lo tanto, era conveniente dilucidar si el tratamiento de acupuntura eficaz de la edad adulta también es aplicable a la infancia.Mediante un diseño con repetición triple de medidas (pre y postratamiento, y a los 4 meses) se estudiaron la intensidad de los síntomas, la función pulmonar, la calidad de vida relacionada con la enfermedad (PAQLQ) y el nivel de ansiedad (STAIC) de 43 pacientes tratados con acupuntura y 42 pacientes de referencia. Además de realizar ejercicios físicos para el asma, terapia climática y entrenamiento del comportamiento, el grupo de acupuntura la recibió según un esquema estandarizado (12 sesiones de 30 min).Después de la acupuntura, manteniendo o reduciendo la medicación establecida, se observó una reducción significativa (p < 0,05) de la frecuencia de la disnea matutina y de la dificultad inspiratoria, así como un efecto positivo sobre el nivel de ansiedad. Los pacientes con asma persistente moderada tratados con acupuntura mostraron adicionalmente una reducción de la obstrucción inducida por el ejercicio (Dif. FEV1 %).Tras la aplicación aditiva de acupuntura se observaron cambios significativos en la función pulmonar en cuadros asmáticos graves, así como una reducción de la ansiedad que se mantuvo durante meses.During rehabilitation children and adolescents with bronchial asthma suff er from physical and mental stress in spite of receiving their asthma medication, or demonstrate poor therapy compliance. The randomized controlled trial evaluates the eff ectiveness of acupuncture in the course of inpatient rehabilitation of children and adolescents with mild to severe persistent bronchial asthma.In a longitudinal study design (pre-, post-, 4 month-follow-up) the eff ects of additional acupuncture on symptom frequency and severity, lung function, medication, quality of life (PAQLQ), general and asthma specific level of anxiety (STAIK) were examined in 43 acupuncture and 42 control patients. Apart from asthma sport, climate therapy and behavioral training, the acupuncture group was given acupuncture treatment according to a standardized needle pattern (12 × 30 min).After acupuncture the frequency of morning breathlessness and inhalation difficulty decreased signifi-cantly (p < 0.05) with equal or reduced medication. Patients treated with acupuncture also showed a tendency towards reduced anxiety levels. Patients of the acupuncture group with moderately persistent asthma demonstrated an additional decline of workload-induced obstruction (FEV1 Diff. %).Add-on acupuncture was able to achieve signifi cant improvements in lung function, especially in severe asthma, as well as a sustained reduction of anxiety scores.

Peripheral arterial disease in heterozygous familial hypercholesterolemia: no difference between patients with and without partial ileal bypass

We evaluated lower limb arterial circulation in 37 patients with heterozygous familial hypercholesterolemia using strain-gauge plethysmography. Nineteen patients were initially allocated to surgical therapy (ileal bypass operation), and 18 control patients were treated conservatively. After a follow-up period of 3–12 years (mean 10 yrs) the surgically treated patients had significantly lower serum total (9.4 vs. 11.9 mmol/1, P < 0.001) and LDL (6.2 vs. 8.1 mmol/1, P < 0.01) cholesterol and apoprotein B levels and higher HDL cholesterol (1.2 vs. 1.0 mmol/1, P < 0.05) and apoprotein A-I levels compared with controls. There was no significant difference in the prevalence of intermittent claudication (16 vs. 6%) or coronary heart disease (68 vs. 61%) between the operated and control groups. The ankle-arm systolic blood pressure ratio was pathologically low in 53% of the operated and 72% of the control patients, and the toe-arm pressure ratio in 50% and 44%, respectively. These differences or the differences in the mean ankle-arm and toe-arm pressure ratios between the groups were not significant. The toe-ankle pressure gradient was normal in all but 2 patients indicating that atherosclerotic changes predominantly affect the more proximal arteries in familial hypercholesterolemia. Patients with peripheral arterial disease could not be differentiated by serum lipoprotein levels, blood pressure or the presence of coronary heart disease. However, smoking was more prevalent (38% vs. 0%, P < 0.05) in patients with impaired peripheral circulation. We conclude that asymptomatic peripheral arterial disease is quite common in familial hypercholesterolemia, and that smoking increases its risk. It seems to be a relatively stable disease, not easily affected by hypocholesterolemic treatment.

Predictors of total and low-density lipoprotein cholesterol change after partial ileal bypass

POSCH is a prospective, randomized secondary intervention trial examining the effect of maximal lipoprotein modification achieved by partial ileal bypass on overall mortality and the course of coronary heart disease. In the initial 189 surgical patients, total cholesterol levels decreased from 256.7 +/- 2.6 mg/dl to 166.6 +/- 2 mg/dl, and low-density lipoprotein cholesterol levels decreased from 181.5 +/- 2.7 mg/dl to 94.1 +/- 1.7 mg/dl 3 months after operation. These significant decreases were sustained through 5 years of follow-up (p less than 0.001). The total cholesterol level was 29.2 +/- 0.9 percent lower and the low-density lipoprotein cholesterol level was 43.2 +/- 1 percent lower at 5 years compared with the baseline level. Decreases of similar magnitude were seen in each of the common WHO lipoprotein phenotypes. The baseline total cholesterol level was the only significant independent preoperative predictor of the 5 year total cholesterol level (correlation coefficient 0.547; p less than 0.001), and the baseline low-density lipoprotein cholesterol level was the only significant independent preoperative determinant of the 5 year low-density lipoprotein cholesterol level (correlation coefficient 0.599; p less than 0.001). These relationships are expressed by the following equations: 5 year total cholesterol = 0.54 X baseline total cholesterol + 42.3, and 5 year low-density lipoprotein cholesterol = 0.455 X baseline low-density lipoprotein cholesterol + 19.2. The decrease in total and low-density lipoprotein cholesterol levels after partial ileal bypass are greater than reported by any trial of drug or diet intervention, including the Lipid Research Clinics Coronary Primary Prevention Trial which examined cholestyramine. Estimation of the change in total and low-density lipoprotein cholesterol levels after partial ileal bypass can be made based on preoperative lipid analysis and is essential in comparing different therapeutic modalities and assessing the role of partial ileal bypass among strategies aimed at lowering coronary heart disease risk.

Fecal and biliary bile acid composition after partial ileal bypass operation.

Biliary and fecal bile acid composition was studied in 13 patients 3-12 years after a partial ileal bypass operation and in 10 unoperated controls, all with heterozygous familial hypercholesterolemia. Three operated patients were taking cholestyramine. The relative amount of cholic acid in the bile was decreased at the expense of chenodeoxycholic acid in the operated subjects. Chenodeoxycholic acid content of the bile correlated negatively with the fractional cholesterol absorption, suggesting that in compromised absorption chenodeoxycholic acid is absorbed more efficiently than cholic acid. Despite a ninefold increase in total bile acid synthesis the cholic/chenodeoxycholic acid synthesis ratio was not significantly different in the operated and control subjects. However, the lower the chenodeoxycholic acid synthesis the higher was the proportion of deoxycholic acid in the bile and feces, suggesting regulation of chenodeoxycholic acid synthesis by deoxycholic acid. Ileal exclusion had increased the proportion of primary bile acids in the feces from below 10 to over 50%. Despite increased fecal water excretion the concentration of fecal total and dihydroxy bile acids was higher in the operated than in control subjects. However, the fecal concentration of the potentially cancer-promoting bile acids, deoxycholic acid and lithocholic acid, was not increased in the operated subjects. In the operated subjects, fecal water output was positively correlated with total bile acid and chenodeoxycholic acid synthesis. It is concluded that the severe bile acid malabsorption caused by ileal exclusion activates the synthesis of both primary bile acids in similar amount. However, after ileal exclusion the relative amount of cholic acid in the bile is decreased, obviously because loss of ileal absorption predominantly affects the absorption of cholic acid.

The Partial Ileal Bypass Operation Does Not Cause Essential Fatty Acid Deficiency

Recent studies have indicated that ileal resection may lead to essential fatty acid deficiency, as demonstrated by plasma fatty acid composition. In the present study the serum cholesterol ester fatty acid composition was determined in patients who had undergone a partial ileal bypass operation several years earlier. The mean length of ileal exclusion was 2.0 m (range, 1.4-2.5 m). The patients with ileal bypass had severe bile acid malabsorption and slight fat malabsorption (fecal fat, 16 g/day). The fatty acid composition of serum cholesterol esters in the patients with ileal exclusion was identical with that of matched controls; for example, linoleic acid comprised 58% of the C14-18 fatty acids in the control patients and 61% in the patients with ileal bypass. It is concluded that exclusion of the distal third of a healthy small bowel does not cause essential fatty acid deficiency.

Program on surgical control of the hyperlipidemias (POSCH): Recruitment experience

The Program on Surgical Control of the Hyperlipidemias (POSCH) is an investigator-initiated NHLBI grant-funded secondary coronary heart disease intervention trial using partial ileal bypass (PIB) for lipid reduction. Randomization started in September 1975 and ended in July 1983 with enrollment of 838 participants (421 surgery, 417 controls). The trial is scheduled to reveal the atherosclerosis impact of the lipid changes in 1990, at which time the average individual in the program will have been followed for 9.6 years. Initially, the magnitude of the recruitment task was greatly underestimated. An area containing 500,000 people was judged to be sufficient to randomize one patient per month. Actually, a population of 2.4–10.5 million, depending upon proximity to a clinic, was needed to achieve this goal. The study design was changed in 1981, due to recruitment costs, with reduction of the number of individuals to be randomized from 1000 to 838 and with extension of the duration of minimum follow-up from 5 to 7 years. Only with the development of a uniform model clinic concept, with specified levels of performance calculated from actual recruitment data, did accrual of patients into the trial become predictable and achievable. Some of the recruitment delays in POSCH were related to problems, in part generic to the existent grant funding mechanism and associated with decisions made by NHLBI and its Advisory Council. These delays were manifested by denial of reallocation of approved funds to initiate replacement clinics for discontinued ones, an 18-month delay in implementation of a protocol change in lipid criteria suggested by the Data M Monitoring Committee, and a 2-year delay in the starting date for the fourth active clinic.

To perfuse or not to perfuse?: Hilary Franklin and Els van der Linden The Netherlands Cancer Institute, Amsterdam(04)

The Program on the Surgical Control of the Hyperlipidemias (POSCH) is a prospective, randomized, controlled, multi-center, secondary, atherosclerosis intervention trial. POSCH addresses the therapeutic arm of the lipid-atherosclerosis theory, i.e. whether lowering of plasma cholesterol is directly related to a reduction in atherosclerosis risk. In this trial, lipid modification is accomplished by the partial ileal bypass operation.Between 1975 and 1983, 838 patients were randomized into this study. All patients were between 30 and 64 years of age, had survived one and only one electrocardiogram and enzyme-documented myocardial infarction; and had a total plasma cholesterol of at least 220 mg/dl or a low density lipoprotein (LDL)-cholesterol of at least 140 mg/dl if the total plasma cholesterol was between 200 and 219 mg/dl after a minimum of 6 weeks of dietary fat and cholesterol restriction. The primary response variable in POSCH is overall mortality. Secondary endpoints include fatal and non-fatal myocardial infarctions, serial electrocardiographic changes, and, most importantly, sequential coronary arteriography changes. The minimum follow-up is currently planned to be 7 years. Study analyses will be made primarily on the “intention to treat” basis.This paper is the first detailed presentation of POSCH design and methodology. Included are descriptions of study design, implementation, and data collection, including data processing, quality assurance/quality surveillance, and patient safety monitoring. POSCH seeks to demonstrate a significant reduction in overall mortality by lipid modification and to validate the use of coronary arteriographic change as a surrogate endpoint for change in coronary heart disease risk.

Effects of partial ileal bypass on the progression of atherosclerotic lesions in WHHL rabbits

At an age of 40 weeks, 9 WHHL rabbits were necropsied as a baseline control group for evaluating aortic and coronary atherosclerosis. An additional 18 WHHL rabbits of the same age underwent either a partial ileal bypas (PIB) or a sham operation. Serum cholesterol concentrations were significantly lower in PIB rabbits than in sham-operated rabbits, mean postsurgical values being 7.9 ± 2.3 mmol/l and 13.2 ± 2.4 mmol/l, respectively. This effect was mainly due to a lower LDL-cholesterol concentration. Serum triglycerides remained unaffected. Thirty weeks after surgery the PIB and sham rabbits were necropsied and atherosclerosis was evaluated. Progression of atherosclerotic plaque size in the sham group was most prominent in the aortic arch. PIB largely prevented this progression. The frequency of plaque complications in the aortic arch also increased in the sham groups. Here, no significant improvement was found in the PIB group. Extensive examination of the heart showed some affected coronary arteries in every 40-week-old WHHL rabbit. Progression of coronary atherosclerosis during the postsurgical period was small in both sham and PIB groups. However, while PIB did not affect the plaque size, it significantly reduced the number of coronary arteries affected.

Efficacy of Mevinolin as Adjuvant Therapy for Refractory Familial Hypercholesterolaemia

Mevinolin, a potent inhibitor of cholesterol synthesis, was used as a therapeutic adjuvant in patients with refractory familial hypercholesterolaemia for an average period of 13 months. Sustained decreases in serum cholesterol of 23 and 31 per cent were achieved by doses of 20 mg and 40 mg/day respectively in 13 heterozygotes already on cholestyramine or after partial ileal bypass. Administration of 80 mg/day to three patients undergoing plasma exchange reduced peak serum cholesterol levels by 11.5 per cent in two homozygotes and by 17 per cent in a double heterozygote for familial hypercholesterolaemia and type III hyperlipoproteinaemia. The decrease in cholesterol was largely confined to low-density lipoprotein and no significant changes occurred in serum triglyceride or high-density lipoprotein cholesterol. Mevinolin was well-tolerated except in one patient who developed myositic symptoms; asymptomatic, transient elevations of serum enzymes were observed in five others. Short and long Synacthen tests showed no evidence that the drug impaired adrenocortical response to ACTH. These results indicate that mevinolin provides a safe and highly effective means of reducing LDL levels in patients with heterozygous familial hypercholesterolaemia refractory to conventional treatment but is less useful in homozygotes.

Long-term effects of partial ileal bypass on the health status of rabbits.

Partial ileal bypass (PIB) surgery is a method for the treatment of familial hypercholesterolaemia in man. Since the rabbit is frequently used as an animal model in experimental studies on PIB, we have investigated the long-term effects of this surgical procedure on the health status of rabbits. Forty-eight weeks after surgery plasma and liver cholesterol levels were decreased by about 40%. The inner diameter of the bypassed ileum was drastically reduced, unlike its length. The bypassed segment did not show clear histological abnormalities. The microflora of the caecum was similar in control and PIB rabbits. PIB did not influence liver histology. The bile of the rabbits with PIB was less lithogenic than that of control animals. Blood haemoglobin levels, haematocrit values and plasma concentrations of alkaline phosphatase, alanine aminotransferase, gamma-glutamyl transferase and lactate dehydrogenase were not changed after PIB. Plasma levels of albumin, creatinine, calcium, phosphorus, vitamin B12 and folic acid were not significantly affected by PIB. Rabbits with PIB had significantly higher plasma levels of bilirubin and zinc than control rabbits, but plasma vitamin E concentrations were significantly lower. These results may be of importance for further studies on the effects of PIB in rabbits.

Effect of partial ileal bypass on ileum morphology in cholesterol-fed pigs.

We have studied ileum morphology in pigs 3.5 months after partial ileal bypass (PIB) surgery. PIB caused a reduction in the length of the bypassed ileum by 60%, while the circumference was decreased by about 70%. We did not find evidence for dilatation of the functional, neo-terminal ileum. These results in pigs are contrary to those found earlier in rabbits. This may be of importance concerning the choice of animal model to study the effects of PIB.