The A-to-Z Trial: Methods and rationale for a single trial investigating combined use of low-molecular-weight heparin with the glycoprotein IIb/IIIa inhibitor tirofiban and defining the efficacy of early aggressive simvastatin therapy.

BACKGROUND: The A-to-Z Trial is an ongoing international, multicenter, randomized study designed to investigate 2 issues concerning contemporary care of patients with acute coronary syndromes (ACS). The first issue is whether the use of low-molecular-weight heparin versus unfractionated heparin affects outcomes and safety when used as a therapy adjunctive to baseline treatment with tirofiban and aspirin in patients with non-ST-elevation (nSTE) ACS. The second issue is whether early use of an aggressively dosed statin is superior to a current trial-based "accepted care" regimen of a lower-dose statin started 3 to 6 months after an acute event. METHODS: The study is conceptually and functionally divided into 2 sequential parts-the "A" Aggrastat and "Z" Zocar phases. The primary A-phase end point is a composite of all-cause mortality, myocardial infarction (MI), and documented refractory ischemia at 7 days. Both nSTE-ACS patients from the A phase and patients with ST-elevation ACS who meet specific risk criteria are eligible to enter the subsequent "Z" (Zocor) chronic phase (Z phase). The primary end point of the Z phase is a composite of cardiovascular death, MI, readmission for ACS, and stroke. The trial will continue until 970 primary events have occurred in the Z-phase population. CONCLUSION: This trial is evaluating 2 temporally connected sequences of phamacotherapy for ACS. At completion, trial results will provide definitive evidence regarding efficacy and safety of early, intensive statin therapy and better define the role of low-molecular-weight heparin in patients with nSTE ACS.

Insulin stimulates receptor-mediated uptake of apoE-enriched lipoproteins and activated alpha 2-macroglobulin in adipocytes.

The low density lipoprotein receptor-related protein (LRP) is a cell surface receptor that binds and internalizes several macromolecules including apolipoprotein E-enriched remnant lipoproteins and protease/antiprotease complexes such as activated alpha 2-macroglobulin. Its function has been studied primarily in cultured fibroblasts and in liver. In the current studies, we provide evidence that LRP is present on the surface of primary adipocytes isolated from rat epididymal fat pads. The activity of the receptor increases 2-3-fold within minutes after the adipocytes are exposed to physiological concentrations of insulin as indicated by an increase in the uptake of 125I-labeled activated alpha 2-macroglobulin. There is a corresponding increase in the uptake of [3H]cholesteryl esters from radiolabeled apoE-enriched beta-very low density lipoprotein. The latter uptake was inhibited by an antibody against LRP and by a fusion protein containing the 39-kDa protein, also called receptor-associated protein, a known inhibitor of LRP function. In vivo, rats that had been fed ad libitum accumulated approximately 24-fold more chylomicron cholesteryl esters in their epididymal fat pads than did fasted control animals. We suggest that insulin stimulation of LRP, in a synergistic action with lipoprotein lipase, increases the endocytic uptake of cholesteryl esters and triglycerides from remnant lipoproteins in postprandial adipocytes.

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.

Treatment of children with homozygous familial hypercholesterolemia: safety and efficacy of low-density lipoprotein apheresis.

We evaluated the safety and efficacy of dextran sulfate low-density lipoprotein (LDL) apheresis in the treatment of three children (aged 6, 7, and 10 years) with severe familial homozygous hypercholesterolemia and undetectable LDL receptor activity. A total of 35 double plasma volume procedures were performed. The ranges of the mean decreases of the three patients in plasma lipid concentrations after LDL apheresis (p less than 0.0001) were as follows: total cholesterol, 76% to 79%; LDL-cholesterol, 78% to 81%; very low density lipoprotein cholesterol, 69% to 75%; high-density lipoprotein cholesterol, 27% to 40%; and triglycerides, 34% to 68%. There were statistically significant but clinically and biologically irrelevant changes in hematologic indexes, serum chemistry values, immunoglobulin levels, complement activity, and plasma concentrations of fat-soluble vitamins. Simple correlation analysis of the variables affecting total cholesterol removal showed significant correlation coefficients (r values) for preapheresis total cholesterol values (r = 0.70; p less than 0.01) and preapheresis LDL-cholesterol values (r = 0.61; p less than 0.01). A multiple regression model explained 82% of the variance based on the preapheresis cholesterol concentration, volume of whole blood processed, and the serum albumin concentration. Side effects of the LDL-apheresis treatments were rare and included abdominal cramping and urticaria. Two procedures were aborted because of intravenous access problems in the younger children. This study confirms that LDL apheresis using a dextran sulfate affinity column is efficacious in rapidly lowering total and LDL-cholesterol concentrations. Furthermore, the procedure is safe and well tolerated by children as young as 6 years of age. This treatment may prevent the progression of atherosclerosis in children with homozygous familial hypercholesterolemia and may therefore avert early death.

Clinical considerations regarding treatment of hypercholesterolemia in the elderly.

Therapy for hypercholesterolemia has been shown to reduce the risk for coronary heart disease in middle-aged men. Current guidelines for detecting and treating hypercholesterolemia in adults render large numbers of elderly patients eligible for medical intervention. The elderly are a heterogeneous group of individuals who differ widely in their ability to function physically, behaviorally, cognitively and emotionally. Not all elderly patients qualify for cholesterol-lowering therapy. Decisions regarding diagnostic and therapeutic interventions should be based on the physiological age of the patient rather than the chronological age, and on the presence and severity of concomitant disease, mental status and cognitive ability, as well as on the patient's expectations from medical care. Suggestions for dietary therapy and drug therapy in the elderly are provided. The objectives and potential benefits of therapy are described. Based on the information currently available, it is concluded that the elderly are likely to benefit from cardiovascular risk factor modification and should not be denied cholesterol-lowering therapy simply on the basis of their chronological age.

The low density lipoprotein receptor in Xenopus laevis. II. Feedback repression mediated by conserved sterol regulatory element.

The 5'-flanking regions of the two low density lipoprotein (LDL) receptor genes in Xenopus laevis contain three repeat sequences that are virtually identical to the repeats that mediate sterol-regulated transcription of the human LDL receptor gene. Like their human counterparts, Xenopus repeats 1 and 3, but not repeat 2, bind the transcription factor Sp1 and thus probably function as positive transcription elements. Xenopus repeat 2, like human repeat 2, contains all of the nucleotides that are required for sterol regulation. Administration of sterols repressed Xenopus LDL receptor mRNA in cultured A6 kidney cells and in the liver of intact frogs. In frogs this repression was associated with a 2-fold increase in plasma LDL levels. Xenopus LDL contains a protein corresponding in size to human apoB-100, a ligand for the LDL receptor. We found no evidence that frog plasma contains B-48, nor did we observe a clear-cut protein corresponding to apoE. We conclude that the structural gene for the LDL receptor has been under sterol-mediated regulation at least since the time of amphibian development more than 350 million years ago.

Pathobiology of human familial hypercholesterolaemia and a related animal model, the Watanabe heritable hyperlipidaemic rabbit.

Defective expression of low density lipoprotein (LDL) receptors is the basic genetic defect in human familial hypercholesterolaemia (FH) and its animal counterpart, the Watanabe heritable hyperlipidaemic (WHHL) rabbit. The pathologic manifestations of human FH were evaluated based on the study of material from six subjects with homozygous FH and a review of the literature. This analysis indicated that homozygous FH is characterized by accelerated atherosclerosis and prominent lipid accumulation in macrophages and other stromal cells of the aortic and mitral valves, skin, tendon, and, variably, in other extravascular sites. Disease progression was studied in the WHHL rabbit. From birth to 1 year, WHHL rabbits show evidence of progressive disease of the aorta with accumulation of birefringent lipid in intimal lesions, including fatty streaks, raised foam cell lesions, and plaques (atheromas), as well as in the media. At 1-2 years, WHHL rabbits develop coronary atherosclerosis and focal extravascular lipid deposits, including subcutaneous and tendinous xanthomas. Vascular lesion development is associated with adhesion of monocytes and other leucocytes to the endothelium. The cells of the intimal lesions are lipid-containing macrophages, smooth muscle cells and foam cells. Most of the intracellular lipid is in the form of non-membrane-bound neutral lipid droplets indicating that the cytoplasm is the major site of lipid storage. Similar ultrastructural features are shown by human FH lesions. Observations are reviewed regarding therapeutic approaches aimed at altering the pathologic expression of familial hypercholesterolaemia, including the negative results of treatment of WHHL rabbits with the calcium-channel antagonist, verapamil, and omega-3 fatty acids.

Long-term clinical tolerance of lovastatin and simvastatin.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors are gaining widespread use in the treatment of hypercholesterolemia. Clinical experience with lovastatin, which is approaching 4 years in many patients, indicates that it is well tolerated. Short-term adverse effects have usually been self-limited and have included abdominal pain, cramps, bloating, and flatus in 4-6% of cases. Raised hepatic transaminases and myopathy have occurred in 1.3 and 0.1% of cases, respectively; both, however, are reversible upon discontinuation of drug. To date, there is no evidence that lovastatin adversely affects the human lens. Overall, the drug has been well tolerated by the vast majority of patients over the long term. Early clinical experience with simvastatin shows a pattern and frequency of side effects similar to that reported with lovastatin.

Cholesterol education implications for clinical practice.

It is well established that an elevated plasma cholesterol level is a major risk factor for coronary heart disease (CHD). Furthermore, results from several clinical trials indicate that therapeutic reduction of high-risk plasma cholesterol levels is followed by a reduction in CHD risk. The National Cholesterol Education Program (NCEP) was launched to enhance the detection of individuals with increased risk for CHD due to elevated plasma cholesterol levels, and to provide guidelines to clinicians for the detection, evaluation and treatment of these high-risk individuals. The key features of the NCEP are described and the guidelines for the detection, evaluation and treatment of high blood cholesterol in adults are summarized. Appropriate treatment of high-risk individuals includes reduction of elevated cholesterol levels and control of other cardiovascular risk factors. Diet therapy is the first step in control of elevated plasma cholesterol levels. In high-risk individuals who do not respond adequately to diet therapy, drug treatment should be considered. Clinical judgment must be used to individualize treatment in each patient. Better detection and control of elevated cholesterol levels and other cardiovascular risk factors should spare high-risk individuals from morbidity and mortality associated with premature CHD.

Portacaval shunt and liver transplantation in treatment of familial hypercholesterolemia.

Portacaval shunt surgery and liver transplantation have been used to treat patients with severe familial hypercholesterolemia (FH). These operations have usually been performed on patients with homozygous FH, but portacaval shunt surgery has also been used in several patients with the heterozygous form of the disease. Portacaval shunt surgery lowers the low density lipoprotein (LDL) cholesterol level by 25% or more in about 80% of patients. The main effect of the operation is to lower the LDL apolipoprotein (apo) B-100 production rate, but there is little effect on the fractional rate of clearance of this apolipoprotein. The operation is only palliative because significant hypercholesterolemia remains after surgery. Liver transplantation restores LDL receptor activity to over 60% of normal, which results in an increase in the fractional catabolic rate (FCR) and a decrease in the synthetic rate of LDL apo B-100. Both metabolic changes cause the LDL cholesterol level to drop by about 80%. After transplantation, homozygotes are also more responsive to certain cholesterol-lowering drugs. It is concluded that liver transplantation is more effective than portacaval shunt surgery for treating homozygous FH. However, liver transplantation should be reserved for those patients who cannot produce functioning LDL receptors and who do not respond to more conservative forms of therapy.

Therapeutic control of hyperlipidemia in the prevention of coronary atherosclerosis: a review of results from recent clinical trials.

The link between elevated plasma cholesterol levels and coronary atherosclerosis is now well established. During the past decade, results from therapeutic trials indicate that control of hypercholesterolemia does result in lower cardiovascular risk. Many of these results were obtained in hypercholesterolemic, middle-aged men. Comparable data in women are not available but it is inferred that they would also benefit from cholesterol reduction. Results from the Coronary Drug Project, extended over 15 years, indicate that lipid-lowering therapy with niacin for 5 years was associated with a decrease in total mortality as well as mortality from coronary heart disease. In the studies performed for shorter periods (5 to 7 years), therapy lowered only cardiovascular morbidity and mortality but had no beneficial effect on total mortality. A reduction in cardiovascular risk begins to appear 24 to 28 months after the initiation of therapy and continues to accrue thereafter. The relatively uniform results from recent large-scale clinical trials (Lipid Research Clinics Coronary Primary Prevention Trial, Coronary Drug Project, Helsinki Heart Study) indicate that cholesterol reduction, per se, probably explains the lower cardiovascular morbidity and mortality observed in these trials. As a result of these trials, recent redefinitions of hypercholesterolemia and more aggressive treatment programs have been recommended. These guidelines stress assessment of all cardiovascular risk factors and recommend individualized care of the patient. To control hypercholesterolemia, conservative measures with diet are recommended before therapy with medication is considered. Recent clinical trial experience indicates that the clinician can have significant impact on atherosclerosis by identifying and treating patients with plasma cholesterol levels in the high-risk range.

Lovastatin therapy in receptor-negative homozygous familial hypercholesterolemia: lack of effect on low-density lipoprotein concentrations or turnover.

To determine whether at least part of the fall in low density lipoprotein (LDL) levels during lovastatin therapy might be the result of a reduced secretion of lipoproteins by the liver, three children 6 to 9 years of age with receptor-negative homozygous familial hypercholesterolemia underwent treatment with lovastatin. These patients have no capacity to synthesize LDL receptors. During lovastatin therapy, at a dose of 2 mg/kg/day, there was no decrease in LDL-cholesterol levels, nor was the turnover rate of LDL affected by the drug. The only significant change was a 74% drop in very low-density lipoprotein during treatment. We conclude that lovastatin is not effective in treatment of receptor-negative homozygous familial hypercholesterolemia. The most likely mechanism of action for this drug is to increase LDL receptor activity.

Combination drug therapy for familial combined hyperlipidemia.

STUDY OBJECTIVE: To compare the efficacy of gemfibrozil and colestipol with gemfibrozil and lovastatin in patients with familial combined hyperlipidemia. DESIGN: A prospective, randomized trial. SETTING: An outpatient clinical research center in a tertiary care center. PATIENTS: Seventeen patients with familial combined hyperlipidemia documented by studies of first-degree relatives; nine patients with type 2b hyperlipoproteinemia, and eight patients with type 4 hyperlipoproteinemia. INTERVENTIONS: Baseline lipid, lipoprotein, and apolipoprotein levels were obtained during control periods on diet alone and on gemfibrozil therapy. Patients then received gemfibrozil and colestipol or gemfibrozil and lovastatin in a randomized order. MEASUREMENTS AND MAIN RESULTS: In patients with type 2b hyperlipoproteinemia, gemfibrozil alone significantly reduced total cholesterol by 11%, and low density lipoprotein (LDL)-apolipoprotein B by 18%, did not change LDL-cholesterol, and raised high density lipoprotein (HDL)-cholesterol levels by 26%. Addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 17% and 25%, respectively, compared to gemfibrozil alone. However, colestipol mitigated the HDL-cholesterol raising effect of gemfibrozil and did not further reduce LDL-apolipoprotein B levels. In contrast, addition of lovastatin caused an additional reduction of LDL-apolipoprotein B 19% compared with gemfibrozil alone. In patients with type 4 hyperlipoproteinemia, gemfibrozil alone reduced triglycerides by 40%, raised HDL-cholesterol by 26%, and increased LDL-cholesterol levels by 29%. The addition of either colestipol or lovastatin reduced LDL-cholesterol levels by 34% and 33%, respectively (compared with gemfibrozil alone), but greater reductions of LDL-apolipoprotein B (30% with lovastatin compared with 15% with colestipol, compared with gemfibrozil alone), and increases in HDL-cholesterol levels (8% increase with lovastatin compared with 10% decrease with colestipol, compared to gemfibrozil alone) were seen with the lovastatin combination. CONCLUSIONS: Although gemfibrozil with either colestipol or lovastatin favorably altered lipoprotein levels in patients with hypertriglyceridemia and familial combined hyperlipidemia, the combination of gemfibrozil and lovastatin appeared superior overall.

Uptake of cholesterol-rich remnant lipoproteins by human monocyte-derived macrophages is mediated by low density lipoprotein receptors.

The uptake and degradation of cholesterol-rich remnant lipoproteins, referred to as beta-VLDL, are shown in the present study to be mediated by LDL receptors (apoB,E(LDL) receptors), not by unique beta-VLDL receptors. Human blood monocytes cultured for 5-7 d bound apoB- and/or apoE-containing lipoproteins from different species with affinities equivalent to those demonstrated for the receptors on cultured human fibroblasts. Low density lipoproteins competed effectively and completely with 125I-beta-VLDL for binding to and degradation by monocyte-derived macrophages. Specific polyclonal antibodies to bovine apoB,E(LDL) receptors abolished both LDL and beta-VLDL uptake by normal human monocyte-macrophages. Immunoblots of monocyte-macrophage extracts with these antibodies revealed a single protein in human macrophages with an apparent molecular weight identical to that of the apoB,E(LDL) receptor found on human fibroblasts. Like receptors on cultured human fibroblasts, the apoB,E(LDL) receptors on monocyte-macrophages responsible for 125I-beta-VLDL and 125I-LDL uptake were efficiently down regulated by preincubation of the cells with beta-VLDL or LDL. Finally, monocyte-macrophages from seven homozygous familial hypercholesterolemia subjects were unable to metabolize beta-VLDL or LDL, but demonstrated normal uptake of acetoacetylated LDL. The classic apoB,E(LDL) receptors on human monocyte-macrophages thus mediate the uptake of beta-VLDL by these cells.

The lipoprotein receptor concept.

The interaction of plasma lipoproteins with mammalian cells is facilitated by specific receptors on the cell surface. The chylomicron remnant receptor recognises apolipoprotein E (apo E) and mediates the uptake of chylomicron remnants by the liver. The low density lipoprotein (LDL) receptor recognises lipoproteins containing apolipoprotein B100 or an activated form of apo E. The LDL receptor therefore mediates the uptake of intermediate density lipoprotein (IDL) and LDL by the liver, and it also facilitates uptake of LDL by other tissues. A receptor for high density lipoprotein (HDL) has been postulated to permit the interaction of HDL with the cell surface to remove intracellular cholesterol for transport ultimately to the liver. Knowledge of the structure and function of the chylomicron remnant receptor and the HDL receptor is still incomplete, but extensive information about the physiological importance of the LDL receptor is now available. Cells utilise the LDL receptor to take up and degrade LDL to obtain cholesterol for cellular use. In vivo these receptors affect the plasma LDL-cholesterol level by regulating both the synthesis and catabolism of LDL. Genetic mutations that impair LDL receptor function cause familial hypercholesterolaemia (FH). Patients with FH have elevated LDL-cholesterol levels and are at increased risk for the development of atherosclerosis. Patients with heterozygous FH have 1 abnormal and 1 normal allele at the LDL receptor locus; the normal allele enables them to respond to certain cholesterol-lowering medications by producing more LDL receptors. Patients with homozygous FH have 2 mutant alleles at the LDL receptor locus and lack the genetic capacity to produce any normal LDL receptors.(ABSTRACT TRUNCATED AT 250 WORDS)