In a survey of a healthy population (n = 197), LDL cholesterol, plasma triglycerides and VLDL triglycerides were found to be substantially increased and plasma HDL cholesterol decreased in smokers. The lipid-associated atherogenic risk in smokers as assessed by the LDL/HDL ratio was significantly higher [2.89 (SD 1.18, n = 63)] than in non-smokers [2.38 (SD 0.98, n = 86) P < 0.01]. The lower HDL level found in smokers was explained by a lower HDL-2 subfraction as determined by analytical ultracentrifugation. HDL 2b, 2a and 3a, measured by gradient gel electrophoresis, were all lower in the smokers but this was only significant for HDL 2a. Smoking had no effect on Lp(a) levels. HDL cholesterol and HDL-2 were strongly negatively correlated whereas LDL cholesterol and LDL/HDL ratio were strongly positively correlated with the plasma triglyceride concentration. There was a small but significant reduction in plasma CETP activity [non-smokers 49% t/microliter (SD 17, n = 90), smokers 43% t/microliter (SD 17, n = 66) P < 0.05] but CETP activity was not correlated with any measure of HDL in this population. Smoking was found to be an important independent contributor to the variation in plasma triglyceride, HDL, HDL-2 and LDL/HDL ratio. After correcting for sex, age, BMI, alcohol consumption, oral contraceptive use and plasma triglycerides smoking was still found to be significantly associated with HDL and the LDL/HDL ratio. Upon adjustment for covariant factors the mean differences between smokers and non-smokers for HDL cholesterol, HDL-2 and LDL/HDL were 0.15 mM, 16 mg dl-1 and 0.39 respectively. There appeared to be important sex differences in the influence of smoking on plasma lipoproteins. In women the main impact of smoking was on triglyceride levels and they in turn affected LDL and HDL. In contrast, in men, smoking had little impact on triglycerides and affected HDL more directly. We conclude that smoking cigarettes has an important effect on plasma lipoprotein metabolism through multiple mechanisms.

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...

The effects of colestipol therapy alone (20 g/d) or combined with simvastatin (20 mg/d) were examined in a group of eight male patients with primary moderate hypercholesterolemia (total cholesterol > or = 6.5 mmol/L [> or = 250 mg/dL]) who had undergone coronary artery bypass grafting more than 3 months previously. Colestipol therapy decreased total cholesterol by 14% (P < .001) and LDL cholesterol (LDL-C) by 23% (P < .001), while dual therapy decreased total cholesterol by 38% and LDL-C by 52% (both P < .001 versus baseline). No significant changes were observed in plasma triglyceride, VLDL cholesterol, or HDL cholesterol levels. VLDL subfraction turnovers were conducted at baseline and again on each regimen. ApoB kinetic parameters derived from a multicompartmental model suggested that colestipol therapy resulted in an expansion of the total VLDL apoB pool (36%, P < .05) that was largely due to a fall in the clearance rate of VLDL1 apoB (49%), while the LDL apoB pool decreased 23% as a result of diminished direct LDL input. The model used also revealed that addition of simvastatin to the resin therapy caused increases in the fractional transfer rates of VLDL2 to IDL and IDL to LDL together with a 37% increment in the LDL apoB fractional catabolic rate. Compared with baseline, combined therapy generated falls in both IDL (35%, P = .01) and LDL (37%, P < .04) apoB pools due to enhanced clearance of IDL (214%, P < .03) and reduced total input of LDL (39%, P < .003).

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