Treatment of refractory familial hypercholesterolemia by low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. The Liposorber Study Group.

A subgroup of patients with familial hypercholesterolemia (FH) respond inadequately to standard diet and drug therapy, and are therefore at high risk for the premature development or progression of coronary artery disease. This study evaluated low-density lipoprotein (LDL) cholesterol and lipoprotein (a) removal in a multicenter, controlled trial with a new LDL apheresis procedure (Liposorber LA-15 System). The study comprised patients with FH who had not responded adequately to diet and maximal drug therapy. There were 54 patients with heterozygous FH (45 randomized to treatment and 9 control subjects) and 10 with homozygous FH (all of whom received LDL apheresis). The study included three 6-week treatment phases and a 4-week rebound phase. Treatments were administered at 7- to 14-day intervals. Mean acute reductions in LDL cholesterol were 76% in heterozygous FH patients and 81% in homozygous ones. Time-averaged levels of LDL cholesterol were reduced 41% (243 to 143 mg/dl) in heterozygous FH patients and 53% (447 to 210 mg/dl) in homozygous ones. The substantial acute reduction of lipoprotein (a) (means: 65%, heterozygous FH; 68%, homozygous FH) has not been reported with other therapies. The Liposorber LA-15 System represents an important therapeutic option in FH patients who respond inadequately to diet and drug therapy.     

How effective is drug therapy in heterozygous familial hypercholesterolemia?

The goals of drug therapy in adult patients with heterozygous familial hypercholesterolemia (FH) are directed at reducing plasma concentrations of low density lipoproteins (LDL), with a secondary goal in selected patients to concurrently decrease elevated plasma concentrations of lipoprotein(a), triglycerides, and potentially exert favorable effects on the concentrations of high density lipoproteins (HDL). Desirable goals of therapy are to reduce concentrations of LDL cholesterol to < 130–160 mg/dL in patients without evidence of coronary artery disease, and, in my opinion, to < 100 mg/dL in patients with evidence of coronary artery disease. The bile add sequestrants, cholestyramine and colestipol, reduce LDL concentrations by 23–36%, when given in doses of 4–6 scoops/day, but reduce LDL concentrations to desirable levels in only 10–15% of patients. Similarly, nicotinic acid, in doses of 3–6 g/day, is capable of reducing LDL concentrations by up to 30%, but the majority of patients still remain hypercholesterolemic. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, which include lovastatin, simvastatin, and pravastatin, are the most effective of the currently available drugs and show dose-dependent effects on the concentrations of LDL cholesterol, which decrease by 20–45% in response to these drugs when used over the full dosage range. However, even with these agents, concentrations of LDL cholesterol remain >200 mg/dL in one-third of mate and female patients with heterozygous FH and remain >160 mg/dL in 75–80% of treated patients. Probucol and the fibrates are less effective than the first choice agents discussed above, and these drugs reduce LDL cholesterol concentrations by < 15% in patients with heterozygous FH. Optimal control of LDL concentrations in patients with heterozygous FH necessitates the use of combination drug therapy in most patients. The goals of LDL reduction necessary for primary prevention of premature coronary artery disease are achievable in the majority of patients with heterozygous FH, whereas optimal values for secondary intervention are infrequently attained.     

Familial hypercholesterolemia in Utah kindred with novel R103W mutations in exon 4 of the LDL receptor gene

Heterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein cholesterol levels early in childhood and very early coronary disease in both men and women. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein (LDL) receptor gene. Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 369, causing substitution of Tryptophan for Arginine at codon 103 in exon 4 of the LDL receptor gene. The SSCP method was used to examine seven members of the family recruited for the diagnosis. This method helped to unequivocally diagnose only the proband as heterozygous for this particular LDL receptor mutation while excluding the remaining six individuals from carrier status with FH.     

Liver transplantation for the treatment of homozygous familial hypercholesterolaemia in an era of emerging lipid‐lowering therapies

Homozygous familial hypercholesterolaemia (FH) causes severe premature coronary artery disease because of very high levels of low density lipoprotein (LDL)‐cholesterol. Standard lipid‐lowering drugs and LDL‐apheresis may not be sufficiently effective. Liver transplantation replaces defective LDL receptors and vastly improves the lipid profile, and we present the first report of an Australian adult to receive this treatment. Emerging drug treatments for FH may be alternatives to LDL‐apheresis and transplantation, but long‐term safety and efficacy data are lacking for all of these options.     

Familial defective apolipoprotein B-100: a single mutation that causes hypercholesterolemia and premature coronary artery disease.

Familial defective apolipoprotein B-100 is a recently identified, dominantly inherited genetic disorder caused by a G to A mutation in exon 26 of the apolipoprotein B gene. This creates a substitution of glutamine for arginine in the codon for amino acid 3500 and results in reduced affinity of low density lipoprotein (LDL) to the LDL receptor. We have integrated already published data with hitherto unpublished data from 8 countries and a total of 135 affected individuals from 56 families, in an attempt to focus on the range of expression of this mutation on lipid and lipoprotein levels and on coronary artery disease. The frequency of this mutation may be as high as 1 in 500 to 1 in 700 in Europe and in North America. The vast majority of affected heterozygotes have total and LDL cholesterol levels well above the 95th centile for age and gender; in contrast, high density lipoprotein cholesterol, very low density lipoprotein cholesterol and plasma triglycerides are not affected by the mutation. The risk of premature coronary artery disease in the carriers of the mutation is increased to levels as high as those seen in patients with clinical familial hypercholesterolemia; at age 50, about 40% of males and 20% of females heterozygous for the mutation have developed coronary artery disease. Familial defective apolipoprotein B-100 is thus a significant cause of hypercholesterolemia and premature coronary artery disease in Western societies.     

Long-term efficacy of low-density lipoprotein apheresis on coronary heart disease in familial hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by severe hypercholesterolemia and premature coronary heart disease (CHD). The lower the plasma cholesterol level, the more likely it is that CHD can be prevented or retarded; aggressive cholesterol-lowering therapies may be indicated for FH patients with CHD. This study describes the long-term (6 years) safety and efficacy of intensive cholesterol-lowering therapies with low-density lipoprotein (LDL) apheresis in heterozygous FH patients with CHD. One hundred thirty heterozygous FH patients with CHD documented by coronary angiography had been treated by cholesterol-lowering drug therapy alone (n = 87) or LDL apheresis combined with cholesterol-lowering drugs (n = 43). Serum lipid levels and outcomes in each treatment group were compared after approximately 6 years. Both treatment groups had significant reductions in serum cholesterol, LDL cholesterol, and high density lipoprotein cholesterol levels. LDL apheresis significantly reduced LDL cholesterol levels from 7.42 ± 1.73 to 3.13 ± 0.80 mmol/L (58%) compared with group taking drug therapy, from 6.03 ± 1.32 to 4.32 ± 1.53 mmol/L (28%). With Kaplan-Meier analyses of the coronary events including nonfatal myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, and death from CHD, the rate of total coronary events was 72% lower in the LDL-apheresis group (10%) than in drug therapy group (36%) (p = 0.0088). It is concluded that LDL-apheresis is effective as treatment of CHD in FH heterozygotes, and may become the therapy of choice in severe types of FH.     

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.     

Management of hyperlipidemia in the pediatric population

Opinion statement Heterozygous familial hypercholesterolemia (FH) affects one in every 500 persons and is the most common cause of markedly elevated cholesterol levels in children. Other causes of primary hyperlipidemia include familial combined hyperlipidemia, which is also common (approximately 1%) but not usually manifest until after puberty, and very rare genetic disorders that may lead to severe hypertriglyceridemia and chylomicronemia syndrome. In children with heterozygous FH, the short-term risk of clinical events is low; therefore, management starts with stratification of risk, followed by dietary modification, and in high-risk cases, pharmacologic treatment initiated after puberty. Male gender, a family history of premature coronary heart disease, and level of low-density lipoprotein (LDL) cholesterol above 4.9 mmol/L are important determinants of risk. Trials have shown that statins effectively lower LDL cholesterol levels; in one study, statins restored endothelial function, with no clinically adverse effects. The effects of statins for longer than 2 years have not been studied. The use of bile acid sequestrants (resins) is limited by compliance and side effects. Children with homozygous FH require expert management with LDL apheresis, high doses of effective statins, and cardiologic follow-up. Ezetimibe, the first in a new class of cholesterol absorption inhibitors, may provide additional efficacy in homozygous FH.     

Effects of Low‐Density Lipoprotein Apheresis on Coronary and Carotid Atherosclerosis and Diabetic Scleredema in Patients with Severe Hypercholesterolemia

Abstract: Correlations between serum cholesterol levels and progression of coronary and peripheral atherosclerosis have been found in many recent studies. It has also been demonstrated that aggressive cholesterol‐lowering therapy with low‐density lipoprotein (LDL) apheresis, a method of LDL elimination by extracorporeal circulation, is effective not only for coronary artery disease, but also for systemic circulatory disturbance in severe hypercholesterolemic patients with familial hypercholesterolemia (FH) in particular. We found that LDL apheresis treatment with medical therapy improved coronary atherosclerotic lesions, based on coronary angiography evaluation and histopathological observation, suppressed progression of early carotid atherosclerotic lesions on annual B‐mode ultrasonography, and improved diabetic scleredema in FH patients. This effectiveness of LDL apheresis appears to be due to recovery of vascular endothelial function and improvement of blood rheology. For diseases that are possibly due to circulation disturbance and that are intractable with drugs alone, LDL apheresis may be worth trying, particularly for patients complicated by hyperlipemia.     

Clinical, diagnostic, and therapeutic aspects of familial hypercholesterolemia

Heterozygous familial hypercholesterolemia (FH) is a common inherited disorder of lipoprotein metabolism. FH is characterized by elevated levels of low-density lipoprotein cholesterol, the presence of tendon xanthomas, and premature cardiovascular disease. The underlying molecular defect of FH consists of mutations in the gene coding for the low-density-lipoprotein-receptor protein, detection of which provides the only unequivocal diagnosis. Although the cause of FH is monogenic, there is wide variation in the onset and severity of atherosclerotic disease in these patients. Additional atherogenic risk factors of environmental, metabolic, and genetic origin are presumed to influence the clinical phenotype in FH. Criteria used to identify individuals with FH include a combination of clinical characteristics, personal and family history of early coronary artery disease, and biochemical parameters. Since the introduction in 1989 of statins, which have been shown to be effective and to delay or prevent the onset of cardiovascular disease, drug treatment of FH has greatly improved. New lipid-lowering agents are presently being developed for clinical use. This review provides an update on the clinical, diagnostic, and therapeutic aspects of heterozygous familial hypercholesterolemia.     

Effectiveness of mevinolin on plasma lipoprotein concentrations in type II hyperlipoproteinemia

Patients with low-density lipoprotein (LDL) concentrations in the top 10th percentile of the population (type II hyperlipoproteinemia [HLP]) are at increased risk for premature cardiovascular disease; however, the incidence of myocardial infarction and death can be decreased by LDL cholesterol reduction. Mevinolin, an inhibitor of endogenous cholesterol synthesis, has been shown to reduce LDL cholesterol concentrations in a subset of type II patients with heterozygous familial hypercholesterolemia (FH). Using a double-blind, randomized, crossover, placebo-controlled trial, the safety and efficacy of mevinolin were compared in 24 patients with type II HLP with heterozygous FH (n = 6) or without FH type II HLP (n = 18). Compared with placebo treatment, both apolipoprotein B and LDL cholesterol levels were reduced (p less than 0.01) in both FH and non-FH patients by 28 to 34% with mevinolin treatment. In addition, high-density lipoprotein cholesterol levels were significantly increased (p less than 0.001) in both patients with FH (16%) and those with non-FH type II HLP (14%). Patients had no serious or clinically significant adverse effects. Thus, mevinolin is a useful drug for treatment of most patients with elevated plasma LDL cholesterol concentrations.     

Effect of low-density lipoprotein receptor mutation on lipoproteins and cardiovascular disease risk: a parent-offspring study

Studies on the clinical consequences of different low-density lipoprotein (LDL) receptor genotypes in adult patients have yielded conflicting results. We hypothesized that children with familial hypercholesterolemia (FH) provide a better model to perform genotype-phenotype analyses than adults. We tested this hypothesis and assessed the effect of LDL receptor genotypes on lipoprotein levels and on parental risk of cardiovascular disease (CVD) in a pediatric FH cohort. We identified 75 different LDL receptor mutations in 645 children with heterozygous FH; in these children, null alleles were clearly associated with more elevated LDL cholesterol levels compared to receptor-defective mutations. Familial factors explained 50.4% of the variation in LDL cholesterol levels of this pediatric cohort compared to only 9.5% in adults. Parental CVD risk was not significantly different between carriers of null alleles and receptor-defective mutations (RR, 1.22; 95% CI, 0.76-1.95; p=0.4). The N543H/2393del9 mutation was associated with a less deteriorated lipid profile and the parents had less often CVD relative to parents with other mutations (RR, 0.39; 95% CI, 0.20-0.78; p=0.008). We could confirm that children with FH provide a better model to perform genotype-phenotype analyses. In particular, children with null alleles had significantly more elevated LDL cholesterol levels than carriers of other alleles but this was not associated with higher risk of CVD in the parents. Nonetheless, a specific LDL receptor mutation was associated with less deteriorated lipoprotein levels and a milder CVD risk.     

Genetics of apolipoprotein B and apolipoprotein AI and premature coronary artery disease

Increased low-density lipoprotein (LDL) and decreased high-density lipoprotein cholesterol (HDL-C) predict premature coronary artery disease, as do elevated levels of apolipoprotein B or reduced levels of apolipoprotein AI. Probands were studied of families with common genetic forms of dyslipidaemia to determine if apo B or apo AI define genetic groups and if apo B or apo AI levels relate to premature coronary artery disease risk. Elevated apo B was characteristic of familial hypercholesterolaemia, familial combined hyperlipidaemia (FCHL), and was seen in individuals with elevated Lp(a). Normal apo B levels were seen in familial hypertriglyceridaemia and in 'coronary artery disease with low-HDL cholesterol'. Apo AI levels tended to be low in FCHL and were decreased in 'coronary disease with low-HDL cholesterol'. In familial hypertriglyceraemia, even though HDL-C levels were low, normal apo AI and apo B levels were seen in the absence of premature coronary artery disease. Therefore, in genetic dyslipidaemias elevated apo B levels and reduced apo AI levels (or increased apo B/AI ratio) differ and predict premature coronary artery disease.     

Long-term (14 years) effect of LDL apheresis on obstructive changes in aortocoronary saphenous-vein bypass grafts in a case of heterozygous familial hypercholesterolemia with the LDL receptor proline664 to leucine mutation

A 61-year-old Japanese woman with heterozygous familial hypercholesterolemia (FH), type 2 diabetes mellitus and coronary artery disease underwent coronary artery bypass grafting (CABG) utilizing a saphenous vein graft at the age of 46, in June 1984, 6 months before low density lipoprotein (LDL) apheresis was started. She had received LDL apheresis every two weeks, along with combined drug treatment since the age of 47 (December 1984). She had bilateral xanthelasma and Achilles tendon xanthomas. Her fasting baseline serum total cholesterol and triglyceride level were 464 mg/dl and 57 mg/dl, respectively at the age of 47 when she visited our hospital for the first time. Analysis of the genomic DNA from the patient revealed heterozygous amino acid substitution of Leu for Pro664 in the LDL receptor gene. She was diagnosed as type 2 diabetes mellitus at the age of 53. Combined treatment in the steady state yielded a pretreatment LDL cholesterol level of 230+/-14 mg/dl and a posttreatment level of 57+/-7.6. All grafts were widely patent after as long as 14 years since CABG, suggesting that LDL apheresis combined with drug therapy is highly effective in preventing the occlusion of bypass grafts in a patient with heterozygous FH and type 2 diabetes mellitus.     

Familial aggregation and early expression of hyperapobetalipoproteinemia

Family history is an important predictor of coronary risk. However, this relation, in large part, is not explained by the known risk factors such as systemic hypertension or hyperlipidemia. In the present study, plasma lipid, lipoprotein lipid, and plasma low-density lipoprotein (LDL) apoB levels were measured in 66 offspring (myocardial infarction [MI] offspring) of 24 families in which an index parent had premature coronary artery disease and hyperapobetalipoproteinemia. These results were compared to those obtained in 207 control children and young adults. Univariate analysis revealed that plasma LDL apoB and all other lipid and lipoprotein levels except high-density lipoprotein cholesterol were significantly higher in the MI offspring. Multivariate analysis showed plasma LDL apoB and LDL cholesterol best differentiated the MI offspring from control children and young adults. Of the 66 children, 22 had hyperapobetalipoproteinemia, of whom only 7 had clearly abnormal LDL cholesterol or plasma triglyceride levels. Thus, a substantial portion of children born to a parent with premature coronary artery disease and hyperapobetalipoproteinemia have the same disorder of lipoprotein metabolism.     

Familial hypercholesterolemia in Utah kindred with novel 2412-6 Ins G mutations in exon 17 of the LDL receptor gene

Familial hypercholesterolemia (FH) is a monogenic disorder associated with primary hypercholesterolemia. FH is characterized by autosomal co-dominant inheritance with strikingly elevated LDL-cholesterol, the presence of xanthoma and premature atherosclerosis. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To determine the genetic etiology of the lipoprotein abnormalities, we screened DNA samples from the family for mutations in all 18 exons and the exon- intron boundaries of the low-density lipoprotein receptor (LDLR) gene. Novel point mutations were identified in the proband: a one-base insertion of G to a five-G stretch at nucleotides 2412-6 (codons 783-785), causing a frameshift in exon 17 of the LDL receptor gene. The direct sequencing method was used to examine six members of the family recruited for the diagnosis. This method helped to unequivocally diagnose the five individuals as heterozygous for this particular LDL receptor mutation. This method also helped us to diagnose with FH, or to exclude from carrier status, three children between ages 6 and 11.     

Importance of HDL cholesterol levels and the total/ HDL cholesterol ratio as a risk factor for coronary heart disease in molecularly defined heterozygous familial hypercholesterolaemia.

AIMS: To assess the relationship of the lipid profile to coronary heart disease in a group of heterozygous familial hypercholesterolaemic subjects with similar age, sex, body mass index, prevalence of angiotensin converting enzyme DD genotype and type of low density lipoprotein receptor mutation. METHODS AND RESULTS: A total of 66 molecularly defined heterozygous familial hypercholesterolaemic subjects, 33 of whom had coronary heart disease, were studied. Clinical features, cardiovascular risk factors and lipid parameters were compared in both groups. Familial hypercholesterolaemic patients with coronary heart disease showed significantly lower values of mean plasma HDL cholesterol and a higher total/HDL cholesterol ratio as compared with familial hypercholesterolaemic subjects free of coronary heart disease. Total and LDL cholesterol concentrations were higher in patients with coronary heart disease, without reaching statistical significance. No differences in plasma lipoprotein(a) levels on absolute and log-transformed values were observed between the two groups. In the whole familial hypercholesterolaemia group, plasma HDL cholesterol levels were related to plasma triglyceride values and to LDL receptor gene 'null mutations'. CONCLUSIONS: In familial hypercholesterolaemic subjects of similar age, gender, body mass index, systolic and diastolic blood pressure, and genetic factors that could influence coronary heart disease risk, plasma HDL cholesterol values and total/HDL cholesterol ratios are two important coronary risk factors. Hence, treatment of familial hypercholesterolaemia should focus not only on lowering total and LDL cholesterol levels, but also on increasing HDL cholesterol values for coronary heart disease prevention. More prospective and intervention trials should be conducted to establish the relationship of HDL cholesterol levels and coronary heart disease in familial hypercholesterolaemia.     

Recommendations for the use of LDL apheresis

Plasma exchange has been shown to increase life-expectancy in homozygous familial hypercholesterolaemia (FH) but increasingly is being replaced by LDL apheresis. Several methods are now available for undertaking this procedure, which lowers LDL cholesterol and Lp(a) efficiently and safely when performed weekly or bi-weekly and causes only slight decreases in HDL cholesterol. Hitherto the main clinical indication has been homozygous FH, including children and pregnant women, but there are limited data showing that LDL apheresis has effects on the progression of cardiovascular disease in FH heterozygotes which are similar to those of maximal lipid-lowering drug therapy. Hence it has the potential to be beneficial in hypercholesterolaemic patients with overt coronary disease who are refractory to or intolerant of drugs. It is therefore recommended that LDL apheresis should be the treatment of choice for: (1) all FH homozygotes from the age of seven onwards unless their serum cholesterol can be reduced by >50% and/or decreased to 5.0mmol/l or is decreased by <40% with maximal drug therapy. Apheresis may also occasionally be indicated on a case-by-case basis for patients with lower levels of LDL. (3) LDL apheresis should also be considered for patients with aggressive progressing coronary disease and Lp(a)>60mg/l whose LDL cholesterol remains >3.2mmol/l despite maximal drug therapy.     

Surrogate markers of atherosclerosis: impact of statins

Carotid artery intima-media thickness (IMT) measured by ultrasound has been shown to be correlated with existing cardiovascular disease (CVD) and predictive of CVD in individuals without clinically evident disease. Carotid IMT is now widely used as a surrogate marker for atherosclerotic disease. A number of studies have shown that lipid-lowering therapy with a statin can reduce or reverse carotid IMT progression. The METEOR trial (Measuring Effects on Intima-Media Thickness: an Evaluation Of Rosuvastatin) will examine the effects of aggressive lipid-lowering treatment with rosuvastatin on IMT in mildly hypercholesterolemic low-risk subjects with relatively high IMT values. The results will provide important information on the ability to achieve regression of abnormal IMT with robust reductions in low-density lipoprotein (LDL) cholesterol levels to below current target levels. Another study will examine the effects of potent LDL cholesterol reduction with rosuvastatin in young patients with heterozygous familial hypercholesterolemia (FH). Patients with FH are at increased risk of premature coronary heart disease in association with marked LDL cholesterol elevations, exhibiting a rate of progression of IMT 5x greater than that of low-risk controls without the disorder and early intervention may be the optimal approach to modifying atherosclerosis progression in these patients.     

Familial defective apolipoprotein B versus familial hypercholesterolemia: an assessment of risk

Patients with familial hypercholesterolemia (FH) or familial defective apolipoprotein B (FDB) have severely increased low-density lipoprotein (LDL)-cholesterol levels and increased risk for premature coronary artery disease (CAD). Previous data on FDB patients were collected in patients referred to lipid clinics and were therefore subject to referral bias. We assessed the clinical phenotype of FDB in a population free from selection on CAD to compare the atherosclerotic burden with that of heterozygous FH. The study population was actively recruited in a large-scale screening program for inherited hypercholesterolemia in which FH and FDB heterozygotes were diagnosed by standard molecular techniques. Patients with FH and FDB had significantly higher plasma total cholesterol and LDL-cholesterol levels compared with their unaffected relatives. As with previous findings in FH, in FDB 19% of the carriers and 17% of the noncarriers of apoB mutations would have been misdiagnosed by cholesterol measurement alone, taking the age- and sex-specific 95th percentile as the diagnostic criterion. In FH patients the CAD risk was 8.5 relative to unaffected family members, whereas FDB patients had a 2.7-fold higher risk of CAD than unaffected relatives. FDB patients, free from clinical selection bias, do show lower total and LDL-cholesterol levels and lower CAD risk compared with FH heterozygotes. However, FDB patients are still exposed to a substantially higher CAD risk compared with unaffected relatives.