Role of risk factor management in progression and regression of coronary and femoral artery atherosclerosis

The results of 3 recently completed studies usher in a new era in the treatment of coronary atherosclerosis and its sequelae. In aggregate, these results show that reductions in low density lipoprotein (LDL) cholesterol or reductions in the ratio of total to high density lipoprotein (HDL) cholesterol by either diet or drugs or both are effective in primary and secondary prevention of coronary artery disease (CAD). In the Lipid Research Clinics' Coronary Primary Prevention Trial, reducing levels of LDL cholesterol, regardless of whether the primary intervention was diet or drug, correlated with a reduction in CAD events. In the National Heart, Lung, and Blood Institute's Type II Coronary Intervention Study, CAD progression at 5 years was inversely related to a change in the ratio of HDL cholesterol to total cholesterol. In the Leiden Intervention Trial, cessation of coronary artery atherosclerotic lesion growth correlated with the ratio of total cholesterol to HDL cholesterol. Several trials now under way will test the effects of much more substantial reductions of LDL cholesterol (up to 50%) and increments in HDL cholesterol (up to 25%) on interrupting the progression or inducing the regression of coronary artery atherosclerosis. Even small reductions in the progression of coronary artery lesions or induction of their regression should produce major reductions in morbidity and mortality from CAD. The importance of secondary prevention also extends to patients after coronary artery bypass surgery, because the likelihood of graft occlusion is likewise related to the patient's lipid profile. Further, the importance of primary prevention of atherosclerosis through modification of lipids and lipoprotein cholesterol in the first-degree relatives of young victims of atherosclerosis cannot be overemphasized.     

High-density lipoprotein, low-density lipoprotein and coronary artery disease

Lipoprotein cholesterol data from the Framingham Heart Study show that low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol levels are important in determining risk for coronary artery disease (CAD). Increased LDL and decreased HDL cholesterol levels are associated with an increase in CAD. Such relations are independent of the usual coronary risk factors, such as cigarette use and hypertension. A 1% greater LDL value is associated with slightly more than a 2% increase in CAD over 6 years; a 1% lower HDL value is associated with a 3 to 4% increase in CAD. Even at total cholesterol levels less than 200 mg/dl, lower HDL levels are associated with increased myocardial infarction rates in both men and women. Death from CAD is increased when HDL levels are low, but there is no such relation between HDL level and cancer death. Triglyceride levels were associated with CAD in Framingham men and women, but the association was no longer significant in men after adjustment for HDL levels. The major determinants for greater HDL levels in Framingham participants included female sex, estrogen use, leanness, greater alcohol intake, exercise, abstinence from smoking and lack of diuretic or beta-blocker use.     

Pharmacologic therapy of lipid disorders in the elderly

Older men and women with coronary artery disease, prior stroke, peripheral arterial disease, and extracranial carotid arterial disease with a serum low-density lipoprotein (LDL) cholesterol >125 mg/dL despite diet should be treated with lipid-lowering drug therapy, preferably with statins, to reduce the serum LDL cholesterol to <100 mg/dL. If statin drug therapy does not lower the serum LDL cholesterol to <100 mg/dL in older persons with coronary artery disease, a bile acid binding resin, such as cholestyramine, should be added, since this drug does not increase the incidence of myositis in persons taking statins. The physician should use statins to treat older persons without atherosclerotic cardiovascular disease with a serum LDL cholesterol=160 mg/dL plus one major risk factor, or a serum LDL cholesterol=130 mg/dL plus a serum high-density lipoprotein (HDL) cholesterol <50 mg/dL. Gemfibrozil may be useful in reducing the incidence of coronary events in persons with coronary artery disease whose primary lipid abnormality is a low serum HDL cholesterol level. There are no good data supporting treatment of hypertriglyceridemia unassociated with increased LDL cholesterol or decreased HDL cholesterol for prevention of cardiovascular disease.     

Clinical significance of plasma lipid levels

Epidemiologic studies have established that elevated low-density lipoprotein (LDL) cholesterol values and decreased levels of high-density lipoprotein (HDL) cholesterol are risk factors for coronary artery disease (CAD). Results from clinical trials indicate that reduction in LDL cholesterol decreases the incidence of and reduces the risk of CAD. The National Cholesterol Education Program recently developed guidelines for the evaluation of plasma cholesterol in adults. Initial classification is categorized and based on the following values: less than 200 mg/dl is "desirable" blood cholesterol; from 200 through 239 mg/dl is classified as "moderate-high" blood cholesterol; and greater than or equal to 240 mg/dl is "high" blood cholesterol. Decision-making regarding therapeutic intervention is influenced by the presence of other lipoprotein risk factors, such as reduced HDL cholesterol and elevated lipoprotein (a), and nonlipid factors, including age, sex, hypertension, obesity, smoking, diabetes mellitus, and family or patient history of CAD. Persons with borderline-high blood cholesterol and established CAD or 2 other risk factors as well as those with high blood cholesterol should undergo lipoprotein analysis. LDL cholesterol is the primary lipoprotein to consider when determining treatment goals. Patients with LDL cholesterol levels greater than 160 mg/dl without CAD or 2 other risk factors and those patients with LDL cholesterol greater than 130 mg/dl with CAD or 2 other risk factors are initially managed with dietary therapy. The goal of treatment of hyperlipidemia is to reduce LDL cholesterol to less than 160 mg/dl or to less than 130 mg/dl in patients with established CAD or with 2 other risk factors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Treatment of older persons with hypercholesterolemia with and without cardiovascular disease

Hypercholesterolemia is a risk factor for new coronary events in older men and women. Secondary prevention trials have demonstrated in persons with coronary artery disease (CAD) and hypercholesterolemia that statin drugs reduced in older persons all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. Statins have also been shown to slow progression of coronary atherosclerotic plaques in persons with CAD, to reduce restenosis after coronary stent implantation, and to decrease myocardial ischemia in persons with CAD. Older men and women with CAD, prior atherothrombotic brain infarction, peripheral arterial disease, or extracranial carotid arterial disease and a serum low-density lipoprotein (LDL) cholesterol level higher than 125 mg/dl despite diet should be treated with statin drug therapy to lower the serum LDL cholesterol level below 100 mg/dl. Primary prevention trials have shown that statins were also effective in reducing cardiovascular events in older persons with hypercholesterolemia. On the basis of data from the Air Force/Texas Coronary Atherosclerosis Prevention Study, the physician should consider using statins in persons aged 65-80 years without cardiovascular disease with a serum LDL cholesterol level above 130 mg/dl and serum high-density lipoprotein cholesterol level below 50 mg/dl.     

Cholesterol 2001. Rationale for lipid-lowering in older patients with or without CAD

Statin treatment of men and women age > or = 50 with coronary artery disease (CAD) and hypercholesterolemia reduces the risk of all-cause mortality, cardiovascular mortality, coronary events, coronary revascularization, stroke, and intermittent claudication. The target serum low-density lipoprotein (LDL) cholesterol level is < 100 mg/dL in older patients with CAD, prior stroke, peripheral arterial disease, or extracranial carotid arterial disease and serum LDL cholesterol > 125 mg/dL despite diet therapy. Statins are also effective in reducing cardiovascular events in older persons with hypercholesterolemia but without cardiovascular disease. Consider using statins in patients age 50 to 80 without cardiovascular disease, serum LDL cholesterol > 130 mg/dL, and serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL.     

Pharmacotherapy of disorders of plasma lipoprotein metabolism

Pharmacologic intervention for altering plasma lipoproteins is aimed principally at reducing atherogenesis and thereby preventing coronary artery disease. These drugs should be prescribed only after nonpharmacologic interventions (reduction of saturated fat and cholesterol consumption, weight reduction, aerobic exercise, cessation of cigarette smoking) have failed to achieve an adequate effect. The plasma concentration of the atherogenic low-density lipoprotein (LDL) may be reduced in hypercholesterolemic patients by increasing hepatic LDL receptor synthesis (bile acid sequestering resins, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase inhibitors) or by reducing hepatic very low density lipoprotein synthesis (gemfibrozil, nicotinic acid). LDL concentration may also be reduced by treatment with one of the fibrates (e.g., fenofibrate). Several classes of lipid-lowering drugs also increase the plasma high-density lipoprotein (HDL) cholesterol concentration. In the case of the fibrates, this appears to be principally mediated through an increase in lipoprotein lipase activity. Gemfibrozil additionally stimulates apolipoprotein AI synthesis. The increase in HDL cholesterol produced by nicotinic acid is due primarily to decreased clearance of HDL particles from the circulation. The increase in HDL concentration produced by gemfibrozil was shown in the Helsinki Heart Study to make a major contribution to a reduced incidence of coronary artery disease, independently of that made by the decrease in LDL. The Cholesterol-Lowering Atherosclerosis Study demonstrated that combined therapy with a resin (colestipol) and nicotinic acid can reduce the progression of coronary atherosclerosis and the development of graft lesions in patients who have undergone coronary artery bypass graft surgery.     

Plasma lipid lowering effects of doxazosin, a new selective alpha1 adrenergic inhibitor for systemic hypertension

Hypertension and hypercholesterolemia are 2 major risk factors for atherosclerotic coronary artery disease (CAD). Elevations of both blood pressure and serum cholesterol levels should be reduced to control CAD risk. Doxazosin is a once-daily, long-acting, selective alpha 1-adrenergic inhibitor that is effective for the treatment of essential hypertension. During controlled studies of doxazosin's antihypertensive efficacy, 3 serum lipid parameters were measured; total cholesterol, total triglyceride and high density lipoprotein (HDL) cholesterol. In 10- to 12-week placebo-controlled studies, 142 doxazosin-treated patients were compared with 155 placebo-controlled subjects. Doxazosin patients had an increase of 8.9% in the HDL/total cholesterol ratio (p less than 0.05), whereas total cholesterol, HDL cholesterol and triglyceride levels were not significantly different between the 2 study groups. During a 52-week comparison of doxazosin versus atenolol, doxazosin treatment was associated with a significant decrease in total triglyceride levels (5%; p less than 0.001) and increases in HDL cholesterol levels (3.9%; p less than 0.01) and HDL/total cholesterol ratio (5.4%; p less than 0.0001). Doxazosin is an effective antihypertensive agent that has a favorable impact on serum lipid levels, thereby promoting a beneficial effect on 2 major CAD risk factors.     

Increased circulating malondialdehyde-modified LDL levels in patients with coronary artery diseases and their association with peak sizes of LDL particles

Recent establishment of a sensitive ELISA system using antibodies against malondialdehyde-modified low density lipoprotein (MDA-LDL) made it possible to determine the circulating oxidized lipoprotein levels. Here, we investigated the serum levels of MDA-LDL in 62 patients with coronary artery disease (CAD) compared with the levels in 42 patients without CAD [groups CAD(+) and CAD(-), respectively], which are adjusted for age, serum total cholesterol, LDL and high density lipoprotein cholesterol, and triglyceride levels. Serum MDA-LDL levels were 113.4+/-49.1 IU/L in CAD(+), which were significantly higher than the levels in CAD(-) (85.2+/-22.5 IU/L, P<0.0005). The ratio of MDA-LDL/LDL cholesterol was 0.95+/-0.32 in CAD(+), indicating a significant increase compared with the ratio in CAD(-) (0.68+/-0.19, P<0.0005). The positive correlation of MDA-LDL level and the ratio of MDA-LDL/LDL cholesterol with intima-media thickness in carotid arteries was observed. Age was not clearly associated with the MDA-LDL level (P=0.865). The serum MDA level was positively correlated with LDL cholesterol (P<0.0001) and with triglycerides (P<0.001) and negatively correlated with high density lipoprotein cholesterol (P<0.05). Furthermore, the MDA-LDL level was negatively correlated with the peak size of the LDL particle (P<0.01). The LDL subclasses that were identified by using the sera collected from the subjects by sequential ultracentrifugation showed that the ratios of MDA-LDL/apolipoprotein B in LDL3 and LDL4 were nearly 3-fold higher than those in LDL1 and LDL2 for CAD(+) and CAD(-). These results indicate that the circulating MDA-LDL level is increased in CAD(+), independent of the serum LDL cholesterol level but in association with the peak size of LDL particles. The measurement of serum MDA-LDL level may be useful for the identification of patients with advanced atherosclerosis.     

Effect of exercise training and diet modification on serum lipids and lipoproteins in coronary artery disease patients treated with thiazides

The effects of chronic exercise training and diet modification on serum lipids and lipoproteins were measured in 17 hypertensive males and 41 normotensive males with documented coronary artery disease (CAD). Exercise consisted of aerobic activities which were performed at approximately 75-85% of the symptom-limited maximum heart rate for 30-40 minutes, three times weekly for 3 months. Each participant's diet was also controlled, the recommended daily intake of fat and cholesterol was no more than 40 g/day and 200 mg/day, respectively. Significant increases in estimated VO2max and total cholesterol/high density lipoprotein (HDL) and a significant decrease in serum triglycerides were documented after training. Significant differences in serum cholesterol and triglycerides between the nondiuretic and diuretic patients were also noted. No significant changes were found in low density lipoprotein (LDL), HDL, or body weight. Vigorous aerobic training and diet modification can favorably modify the deleterious effects of diuretic medications on serum triglycerides and total cholesterol/HDL in patients with documented CAD.     

Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography

In a study of 307 white patients who underwent coronary angiography, the relationship of coronary artery disease (CAD) to plasma levels of lipoprotein Lp(a) and other lipid-lipoprotein variables was examined. Lp(a) resembles low-density lipoprotein (LDL) in several ways, but can be distinguished and quantified by electroimmunoassay. CAD was rated as present or absent and was also represented by a quantitative lesion score derived from estimates of stenosis in four major coronary vessels. Coronary lesion scores significantly correlated with Lp(a), total cholesterol, triglycerides, LDL cholesterol, and high-density lipoprotein (HDL) cholesterol levels by univariate statistical analysis. By multivariate analysis levels of Lp(a) were associated significantly and independently with the presence of CAD (p less than .02), and tended to correlate with lesion scores (p = .06). Among subgroups Lp(a) level was associated with CAD in women of all ages and in men 55 years old or younger. An apparent threshold for coronary risk occurred at Lp(a) lipoprotein mass concentrations of 30 to 40 mg/dl, corresponding to Lp(a) cholesterol concentrations of approximately 10 to 13 mg/dl. Plasma Lp(a) in white patients appears to be a major coronary risk factor with an importance approaching that of the level of LDL or HDL cholesterol.     

ASCOT-LLA and the primary prevention of coronary artery disease in hypertensive patients

Although each revision of the US National Cholesterol Education Program guidelines has made increasing provision for the use of global risk assessment in determining need for and intensity of therapy, the guidelines' continued focus on low-density lipoprotein (LDL) cholesterol may result in inadequate or no treatment for individuals at high risk for coronary artery disease (CAD) who do not have substantially elevated LDL cholesterol. However, recent clinical trial evidence has shown that high-risk patients benefit from lipid-regulating therapy regardless of LDL cholesterol level. In the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm, high-risk hypertensive patients had reductions in clinical events despite not having substantially elevated LDL cholesterol at baseline. These results suggest that all hypertensive patients with additional risk factors should receive lipid-regulating statin therapy to prevent CAD events.     

Role of circulating high-density lipoprotein and triglycerides in coronary artery disease: risk and prevention

A substantial body of evidence suggests that circulating levels of high-density lipoprotein (HDL) and certain triglyceride-carrying lipoproteins may, like low-density lipoprotein (LDL), be important risk factors in the development of atherosclerotic coronary artery disease (CAD). Furthermore, both low HDL cholesterol and high triglyceride levels are frequently associated with other CAD risk factors, whose correction, often by hygienic means, may reduce CAD risk without fear of adverse side effects. However, the available evidence is not yet sufficiently coherent and compelling to justify guidelines (analogous to those for LDL cholesterol) for specific pharmacologic treatment of low plasma HDL cholesterol or moderately elevated plasma triglyceride levels to prevent CAD.     

Circulating oxidized LDL is a useful marker for identifying patients with coronary artery disease

Our aim was to determine the usefulness of circulating oxidized low density lipoprotein (LDL) in the identification of patients with coronary artery disease (CAD). A total of 304 subjects were studied: 178 patients with angiographically proven CAD and 126 age-matched subjects without clinical evidence of cardiovascular disease. The Global Risk Assessment Score (GRAS) was calculated on the basis of age, total and high density lipoprotein cholesterol, blood pressure, diabetes mellitus, and smoking. Levels of circulating oxidized LDL were measured in a monoclonal antibody 4E6-based competition ELISA. Compared with control subjects, CAD patients had higher levels of circulating oxidized LDL (P<0.001) and a higher GRAS (P<0.001). The sensitivity for CAD was 76% for circulating oxidized LDL (55% for men and 81% for women) compared with 20% (24% for men and 12% for women) for GRAS, with a specificity of 90%. Logistic regression analysis revealed that the predictive value of oxidized LDL was additive to that of GRAS (P<0.001). Ninety-four percent of the subjects with high (exceeding the 90th percentile of distribution in control subjects) circulating oxidized LDL and high GRAS had CAD (94% of the men and 100% of the women). Thus, circulating oxidized LDL is a sensitive marker of CAD. Addition of oxidized LDL to the established risk factors may improve cardiovascular risk prediction.     

Clinical expression of familial hypercholesterolemia in clusters of mutations of the LDL receptor gene that cause a receptor-defective or receptor-negative phenotype

Seventy-one mutations of the low density lipoprotein (LDL) receptor gene were identified in 282 unrelated Italian familial hypercholesterolemia (FH) heterozygotes. By extending genotype analysis to families of the index cases, we identified 12 mutation clusters and localized them in specific areas of Italy. To evaluate the impact of these mutations on the clinical expression of FH, the clusters were separated into 2 groups: receptor-defective and receptor-negative, according to the LDL receptor defect caused by each mutation. These 2 groups were comparable in terms of the patients' age, sex distribution, body mass index, arterial hypertension, and smoking status. In receptor-negative subjects, LDL cholesterol was higher (+18%) and high density lipoprotein cholesterol lower (-5%) than the values found in receptor-defective subjects. The prevalence of tendon xanthomas and coronary artery disease (CAD) was 2-fold higher in receptor-negative subjects. In patients >30 years of age in both groups, the presence of CAD was related to age, arterial hypertension, previous smoking, and LDL cholesterol level. Independent contributors to CAD in the receptor-defective subjects were male sex, arterial hypertension, and LDL cholesterol level; in the receptor-negative subjects, the first 2 variables were strong predictors of CAD, whereas the LDL cholesterol level had a lower impact than in receptor-defective subjects. Overall, in receptor-negative subjects, the risk of CAD was 2.6-fold that of receptor-defective subjects. Wide interindividual variability in LDL cholesterol levels was found in each cluster. Apolipoprotein E genotype analysis showed a lowering effect of the epsilon2 allele and a raising effect of the epsilon4 allele on the LDL cholesterol level in both groups; however, the apolipoprotein E genotype accounted for only 4% of the variation in LDL cholesterol. Haplotype analysis showed that all families of the major clusters shared the same intragenic haplotype cosegregating with the mutation, thus suggesting the presence of common ancestors.     

Secondary prevention and lipid lowering: results and implications

In a secondary prevention trial conducted by the National Heart, Lung, and Blood Institute, the effect of lipid lowering by drug intervention on the progression of existing coronary artery disease (CAD) was evaluated in type II hyperlipidemic patients. This first randomized, secondary prevention trial compared the effect of cholestyramine and diet with that of placebo and diet in 143 patients over a 5-year period. End points evaluated were progression or regression of CAD, as demonstrated by angiographic changes compared with baseline angiograms. The cholestyramine-treated group demonstrated a significant reduction in total cholesterol and in low-density lipoprotein cholesterol (LDL) levels as compared with placebo, and an 8% increase in high-density lipoprotein cholesterol (HDL). A statistically significant result supporting the use of cholestyramine treatment was found in one category of CAD progression.     

Regulation of low-density lipoprotein particle size distribution in NIDDM and coronary disease: importance of serum triglycerides

Summary An increase of low-density lipoprotein triglycerides (LDL-Tg) was found to be an independent coronary artery disease (CAD) risk factor for non-insulin-dependent diabetic (NIDDM) patients in a recent prospective study. We examined the composition and size of LDL particles in 50 NIDDM men with angiographically verified CAD (NIDDM+ CAD+) and in 50 NIDDM men without CAD (NIDDM+ CAD–) as compared to 50 non-diabetic men with CAD (NIDDM– CAD+) and 31 non-diabetic men without CAD (NIDDM– CAD–). The groups had similar ranges of age and BMI LDL particle size was determined by gradient gel electrophoresis, and LDL was isolated by sequential ultracentrifugation for compositional analyses. Serum Tg was increased in NIDDM patients as compared to non-diabetic subjects (p<0.05), and in patients with CAD as compared to subjects without the disease (p<0.05). LDL cholesterol was lower in NIDDM patients than in non-diabetic subjects (p<0.001). Mean diameter of LDL particles was less than 255 å, but closely comparable in all groups. The presence of NIDDM was associated with increases of Tg and protein but lowering of free cholesterol in LDL (p<0.005 for all). In multivariate regression analyses neither NIDDM nor CAD were associated with LDL particle size, but serum Tg was the major determinant of LDL size in both NIDDM and non-diabetic subjects (p<0.001). When the patients were divided into quartiles according to fasting serum Tg levels, the LDL particle size and free cholesterol content decreased, but Tg and protein contents of LDL particles increased from the lowest to the highest Tg quartile (analysis of variance p<0.001 for all). When the subjects were categorized into two groups according to the median of VLDL-Tg (1.10 mmol/l) LDL size was associated with VLDL-Tg in the high but not in the low VLDL-Tg group. We conclude that in NIDDM patients with or without CAD serum Tg is the major determinant of the properties of LDL particles. The clinical implication is that in NIDDM serum Tg should be as low as possible to prevent atherogenic changes in LDL.Abbreviations NIDDM Non-insulin-dependent diabetes mellitus - CAD coronary artery disease - HDL high-density lipoprotein - LDL low-density lipoprotein - VLDL very-low-density lipoprotein - apoB apolipoprotein B - HL hepatic lipase - LPL lipoprotein lipase - CETP cholesteryl ester transfer protein - PL phospholipids - ANOVA analysis of variance - Tg triglycerides - FC free cholesterol     

Detection and evaluation of dyslipoproteinemia

Screening for dyslipoproteinemias should be undertaken in all individuals older than 20 years of age at least once every 5 years. The initial screening, as recommended by the Adult Treatment Guidelines Panel of the National Cholesterol Education Program, is to determine the concentration of total blood cholesterol. This initial determination can be made on blood obtained in the nonfasting state. Further evaluation of the patient's lipoprotein concentrations is dependent upon the presence of other cardiovascular risk factors. in the absence of definite coronary heart disease, hypertension, diabetes mellitus, a family history of coronary artery disease, cigarette smoking, or severe obesity, the patient with a total blood cholesterol concentration less than 200 mg/dL requires no specific instruction and should have a repeated screening performed within 5 years. Patients with blood cholesterol concentrations greater than 200 mg/dL should have their lipoprotein profiles determined if they have atherosclerotic cardiovascular disease or two other cardiovascular disease risk factors. The lipoprotein profile includes the determination of fasting cholesterol and triglyceride and HDL cholesterol concentrations. From these values, the LDL cholesterol concentration can be calculated. This LDL cholesterol concentration is central in selecting the appropriate therapy. HDL cholesterol concentrations may be useful in evaluating patients with ischemic heart disease. Concentrations of HDL cholesterol less than 35 mg/dL are associated with increased risk for coronary artery disease. Although there is currently no convincing evidence that support the specific treatment of depressed HDL cholesterol concentrations, therapy directed to modulating lipoprotein metabolism in patients with heart disease and low HDL concentrations may be of benefit. Patients with recurrent abdominal pain, pancreatitis, and eruptive xanthomatosis frequently have fasting hypertriglyceridemia concentrations exceeding 1000 mg/dL. These patients should be identified in order to effectively reduce their triglyceride concentrations, which can prevent these complications.     

Apheresis Technology for Prevention and Regression of Atherosclerosis

Abstract: Familial hypercholesterolemia (FH) is a congenital disorder of cholesterol metabolism, which is due to a deficiency in low‐density lipoprotein (LDL) receptors. The homozygous form of FH is especially liable to coronary artery disease (CAD) in youth because of the very high LDL‐cholesterol levels. It is resistant to drug therapy, and LDL‐apheresis is the only practical way of treatment for these patients. Some patients with heterozygous FH also have high LDL‐cholesterol levels that cannot be brought down into the optimum range by any combination drug therapy. We have treated or are treating 10 homozygous and 28 heterozygous FH patients in our hospital or in affiliated hospitals expert in blood purification. Among the 10 homozygous patients, 2 died of myocardial infarction. Only one young female patient is still free of symptoms, and the other patients have been suffering from regurgitation through the aortic valve although they have not experienced myocardial infarction. Rapid rebound of LDL‐cholesterol after each apheresis treatment limits the period during which LDL‐cholesterol is in the optimum range. The use of atorvastatin at a high dose (40 mg/day) was attempted to suppress this rebound. In contrast with good results in receptor‐defective‐type patients, receptor‐negative‐type patients did not show a response in LDL‐cholesterol levels to the statin therapy although there was a slight increase in high‐density lipoprotein (HDL)‐cholesterol with a decrease in very‐low‐density lipoprotein‐triglyceride and ‐cholesterol. Follow‐up study of the patients with heterozygous FH revealed that LDL‐apheresis was effective in lengthening the life expectancy of the patients with pre‐existing CAD, especially those who had received intervention coronary artery bypass grafting (CABG) or percutaneous transluminal coronary angioplasty (PTCA). It was also shown that the use of probucol in combination with LDL‐apheresis was effective in reducing coronary events as shown by the necessity of CABG or PTCA. Clinical data on the effect of LDL‐apheresis, recently reported from some other institutions in Japan, will also be reviewed.     

Rapid isolation of low density lipoprotein (LDL) subfractions from plasma by density gradient ultracentrifugation

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 +/- 28.8 vs. 42.3 +/- 25.7 mg/dl, P less than 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 +/- 92.6 mg/dl in CAD vs. 87.4 +/- 79.6 mg/dl in normal men, P less than 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.