Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p<0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL, (S, 60-400), VLDL 2 (S r 20-60), intermediate density lipoprotein , and LDL (S r 0-12), and metabolic changes were sought in dual-tracer VLDL] and VLDL 2 turnover studies. VLDL, apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL 2 . Similarly, the VLDL 2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p< 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p< 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL 2 and IDL was increased (p<0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL 2 but not VLDL,. {Arteriosclerosis and Thrombosis 1993;13:170-189) KEY and more recently from the Helsinki Heart Study 3 has confirmed the importance of lipid lowering as a means of preventing coronary heart disease (CHD). Since the completion of these studies, more powerful lipid-regulating agents have become available; the most potent of these in terms of low density lipoprotein cholesterol (LDL-C) lowering are the 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors or "statins." This is an important class of lipid-lowering drugs whose remarkable efficacy has been documented in studies of several different groups of patients. 4 " 10 The precise mechanism of action of these compounds, however, has not been fully elucidated. At first it was thought that they affected only LDL via activation of hepatic apolipoprotein (apo) B/E receptors. However, further experience has suggested that they have substantial effects on very low density In general, all statins have weak but significant plasma triglyceride-lowering properties; in type III hyperlipoproteinemic subjects it has been shown that statins can, uniquely among lipid-lowering drugs, correct the compositional abnormality seen in VLDL. 9 Investigations of the kinetic changes underlying the LDL reduction on statin therapy have revealed an unsuspected heterogeneity of response. Many subjects, particularly those with familial hypercholesterolemia (FH), exhibit an increase in apoLDL clearance while on the drug, 13 whereas in others decreas...
Metabolic heterogeneity in low density lipoprotein (LDL) may be detected by examination of the daily urinary excretion rate of radioactivity after injection of trace-labeled lipoprotein. Two distinct pools are observed within LDL. The first (pool A) is cleared rapidly from the plasma, whereas the second (pool B) is catabolized more slowly. In the present study we examined LDL metabolism in seven hypercholesterolemic subjects (six women and one man) before and during fenofibrate therapy. Comparison with normocholesterolemic individuals showed that the pretreatment high LDL levels in the hypercholesterolemic subjects resulted from an accumulation of apoprotein-LDL (apo-LDL) mass in pool B (2,077 ±174 mg versus 787 ±70 mg in normal subjects, p< 0.002). Pool A apo-LDL was present at normal levels (-1,000 mg), although its fractional catabolic rate was reduced (0.39±0.06 versus 0.61 ±0.03 pool/day in normal subjects,p<0.01). Fenofibrate therapy (100 mg t.i.d. for 8 weeks) produced substantial reductions in plasma cholesterol (29%;p<0.001), triglycerides (36%;p<0.001), and LDL cholesterol (30%;p<0.001). The latter was associated with a 30% decrease in circulating apo-LDL mass (2,312 ±200 mg versus 3,279 ±264 mg before treatment, p< 0.005). This resulted from a combination of two effects. First, although overall LDL apoprotein B production did not change, there was a shift from pool B to pool A. Pool A input was 400±74 mg/day pretreatment versus 706±62 mg/day on fenofibrate; pool B input was 422 ±35 mg/day pretreatment versus 258±41 mg/day on the drug. At the same time, catabolism of pool A rose from 0.39±0.06 to 0.66±0.08 pool/day (p<0.05). We hypothesize that the shift from pool B to pool A resulted from a drug-induced decrease in the particle size of very low density lipoprotein made by the liver, which in turn favored the formation of more rapidly catabolized LDL. Overall, the rate of apo-LDL degradation by the receptor route (as detected using a combination of native and 1,2-cyclohexanedione-modified LDL tracers) rose 43% on the drug, whereas the amount cleared by the receptor-independent pathway did not change. Fenofibrate, therefore, appears not only to promote LDL catabolism via the receptor-mediated pathway but also, by lowering plasma triglyceride levels, inhibits the formation of slowly metabolized, potentially atherogenic LDL particles. L ow density lipoprotein (LDL), the major cholesterol carrier in human plasma, plays a critical role in the initiation and progression of atherosclerotic lesions. Until recently, studies of the structure, function, and metabolism 1 of this lipoprotein assumed it to be a homogeneous entity. However, it has now been demonstrated that LDL exists in the plasma of normal and hyperlipidemic individuals as a heterogeneous population of particles that are usually divided into three subtractions on the basis of size and density. -4 Preliminary investigations have indicated that these fractions have distinct properties. LDL-I, the largest and most buoyant, is present in high concentra...
This study examines the kinetic basis for the increment in plasma low density lipoprotein (LDL) levels that accompanies the fenofibrate treatment of severely hypertriglyceridemic (HTG) patients. Seven HTG men with a mean plasma triglyceride level of 1470 mg/dl were treated for 6 weeks. During treatment, their plasma triglyceride level fell by 77% and their cholesterol level by 41%. The fall in very low density lipoprotein (VLDL) cholesterol level was reciprocated by increments in the cholesterol level in both LDL and high density lipoproteins (HDL); the rise in HDL was confined to HDL 3 . LDL catabolism was examined before and during therapy using native and chemically modified tracers in an attempt to distinguish receptor-mediated from nonreceptor-mediated clearance. In their basal state, the hypertriglyceridemic subjects overcatabolized both the native and the modified lipoprotein, implying that the nonreceptor pathways were hyperactive. The mean fractional clearance rate of LDL via the receptor pathway was not significantly different from normal. Fenofibrate therapy corrected the patients' hypercatabolism, reducing the receptor-independent fractional clearance of apo LDL by 50% (from 0.48 to 0.24 pools/day; p < 0.05). The mean fractional catabolic activity of the receptor route did not change, but when the increment in the plasma apo LDL concentration was taken into account, it was clear that the drug treatment was associated with an increase in the net amount cleared by the receptor pathway and with a reduction of lipoprotein uptake into receptor-independent routes. (Arteriosclerosis 5:162-168, March/April 1985)
Objective: To assess the outcome of a policy of emergency percutaneous coronary intervention (PCI) in patients with acute myocardial infarction and electrocadiographic (ECG) evidence of failed reperfusion after thrombolysis. Design: Observational study. Setting: District general hospital. Patients: A total of 109 consecutive patients with acute myocardial infarction who underwent emergency angiography and angioplasty for failed reperfusion diagnosed on the basis of standard ECG criteria. Main outcome measures: In-hospital mortality; death, infarct territory reinfarction, and reintervention by PCI or coronary artery bypass graft (CABG) during follow up; in-lab resource utilisation. Results: At initial angiography, 76 patients had Thrombolysis in Myocardial Infarction (TIMI) trial 0/1 flow and 33 had TIMI 2/3 flow. Fourteen patients were in cardiogenic shock. TIMI 3 flow was established or maintained in 93 patients (85%). Overall in-hospital mortality was 9%. It was 3% in non-shock patients, 50% in shocked patients, and 40% when the procedure was unsuccessful (TIMI 0/1 flow post-procedure). Over a mean follow up of 30 months (>12 months of follow up in all patients) there were 19 further events (one death, five reinfarctions, and 13 revascularisations (nine CABG and four PCI)). The cost of rescue PCI was not significantly higher than comparable elective interventions. Conclusion: A policy of emergency angiography and PCI for failed reperfusion in acute myocardial infarction can be carried out in a hospital without on-site surgical backup with good medium term clinical outcomes.
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