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Background — Peroxisome proliferator-activated receptor α (PPARα) regulates the expression of genes involved in lipid metabolism and inflammation, making it a candidate gene for atherosclerosis and ischemic heart disease (IHD). Methods and Results — We investigated the association between the leucine 162 to valine (L162V) polymorphism and a G to C transversion in intron 7 of the PPARα gene and progression of atherosclerosis in the Lopid Coronary Angiography Trial (LOCAT), a trial examining the effect of gemfibrozil treatment on progression of atherosclerosis after bypass surgery and on risk of IHD in the second Northwick Park Heart Study (NPHS2), a prospective study of healthy middle-aged men in the United Kingdom. There was no association with plasma lipid concentrations in either study. Both polymorphisms influenced progression of atherosclerosis and risk of IHD. V162 allele carriers had less progression of diffuse atherosclerosis than did L162 allele homozygotes with a similar trend for focal atherosclerosis. Intron 7 C allele carriers had greater progression of atherosclerosis than did G allele homozygotes. The V162 allele attenuated the proatherosclerotic effect of the intron 7 C allele. Homozygotes for the intron 7 C allele had increased risk of IHD, an effect modulated by the L162V polymorphism Conclusions — The PPARα gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARα affects atherosclerotic progression directly in the vessel wall.

Background —The −344C allele of a 2-allele (C or T) polymorphism in the promoter of the gene encoding aldosterone synthase (CYP11B2) is associated with increased left ventricular size and mass and with decreased baroreflex sensitivity, known risk factors for morbidity and mortality associated with myocardial infarction (MI). We hypothesized that this polymorphism was a risk factor for MI. Methods and Results —We used a nested case-control design to investigate the relationships between this polymorphism and the risk of nonfatal MI in 141 cases and 270 matched controls from the Helsinki Heart Study, a coronary primary prevention trial in dyslipidemic, middle-aged men. There was a nonsignificant trend of increasing risk of MI with number of copies of the −344C allele. However, this allele was associated in a gene dosage–dependent manner with markedly increased MI risk conferred by classic risk factors. Whereas smoking conferred a relative risk of MI of 2.50 ( P =0.0001) compared with nonsmokers in the entire study population, the relative risk increased to 4.67 in −344CC homozygous smokers (relative to nonsmokers with the same genotype, P =0.003) and decreased to 1.09 in −344TT homozygotes relative to nonsmokers with this genotype. Similar joint effects were noted with genotype and decreased HDL cholesterol level as combined risk factors. Conclusions —Smoking and dyslipidemia are more potent risk factors for nonfatal MI in males who have the −344C allele of CYP11B2.

Background —Lipid-lowering secondary-prevention trials of coronary artery disease (CAD) have implicated triglyceride-rich lipoproteins as the main determinants of angiographic progression after elevated LDL cholesterol levels have been lowered with therapy. The present study focuses on the lipoprotein determinants of angiographic CAD progression in men with low HDL cholesterol concentration as their main baseline lipid abnormality who underwent 32 months of randomized therapy with gemfibrozil or placebo. Methods and Results —Men who had undergone coronary bypass surgery (n=372) completed a randomized, placebo-controlled study with gemfibrozil 1200 mg/d. They were selected primarily for HDL cholesterol levels that corresponded to the lowest third for middle-aged men. Average baseline lipid and lipoprotein levels were serum triglyceride, 1.60; serum cholesterol, 5.17; ultracentrifugally separated LDL cholesterol, 3.43; HDL 2 cholesterol, 0.41; and HDL 3 cholesterol, 0.61 mmol/L. In the gemfibrozil group, these levels were reduced on average by 40%, 9%, and 6% or increased by 5% and 9%, respectively. On-trial IDL and LDL triglyceride and cholesterol levels significantly predicted global angiographic progression, taking into account changes in native segments and in bypass grafts. HDL 3 but not HDL 2 cholesterol concentration was associated with protection against progression, especially focal disease in native coronary lesions. VLDL was the lipoprotein most predictive of new lesions in vein grafts; IDL was also significantly related. Conclusions —This study expands the previous evidence of the triglyceride-rich lipoproteins, especially IDL, as predictors of angiographic progression of CAD but does not negate the significance of mildly elevated LDL levels. Of the HDL subfractions, only HDL 3 was protective in this group of men selected for their low initial HDL levels.

Several large intervention trials have investigated the potential of fibrates to reduce cardiovascular events. The results have varied widely: positive, with gemfibrozil in the primary prevention Helsinki Heart Study (HHS)1 and the secondary prevention Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT)2; positive, with reservations related to an increase in noncardiovascular mortality in the primary prevention World Health Organization trial (clofibrate)3; and mixed, with bezafibrate in the secondary prevention Bezafibrate Infarction Prevention (BIP) study4 and with fenofibrate in the combined primary and secondary prevention FIELD study,5 in which positive outcomes were observed only in certain subgroups. Reasons for the differences between the outcomes of these studies are not immediately apparent. Article p 1556 It emerged in post hoc subgroup analyses of the HHS,6 VA-HIT,7 and BIP8 data that fibrate-induced reductions in cardiovascular events were especially great (of the order of 30% to 50%) in subjects with evidence of insulin resistance or other features of the metabolic syndrome, such as dyslipidemia and increased body weight. However, this finding was not replicated with fenofibrate in the FIELD study.5 In another post hoc analysis of VA-HIT, it was found that diabetics with preexisting cardiovascular disease derived a major reduction in future events when treated with gemfibrozil,7 but again, this was not confirmed with fenofibrate in FIELD.5 The observation that the cardioprotective effects of gemfibrozil in the HHS and VA-HIT studies were substantially greater than those found with other fibrates in the World Health Organization, BIP, and FIELD studies may reflect no more than the play of chance. It may also reflect differences in the populations studied in the trials. However, it is possible that gemfibrozil has protective properties that are lacking in other fibrates or that other fibrates have adverse …

Background Studies have shown that treatment of hyperlipidemia, especially lowering of plasma LDL levels, retards the progression of coronary atherosclerosis and prevents clinical cardiovascular events. No such studies have focused on subjects with low levels of HDL cholesterol. Methods and Results We randomly assigned 395 post–coronary bypass men, who had an HDL cholesterol concentration ≤1.1 mmol/L and LDL cholesterol ≤4.5 mmol/L, to receive gemfibrozil 1200 mg/d or placebo. Coronary angiography was performed at baseline and after, on average, 32 months of therapy. Changes in coronary dimensions were assessed by computer-assisted analysis. Average on-trial serum triglyceride concentrations were 1.69±0.68 and 1.02±0.37, total cholesterol 5.48±0.68 and 4.83±0.63, LDL cholesterol 3.84±0.59 and 3.39±0.56, and HDL cholesterol 0.88±0.15 and 0.98±0.17 mmol/L in the placebo and gemfibrozil groups, respectively (mean±SD, each P P =.009). The equivalent changes in minimum luminal diameters of stenoses were –0.09±0.18 and –0.04±0.15 mm, respectively ( P =.002). A similar, albeit nonsignificant, trend toward treatment benefit was found in the predefined primary study end point, segments unaffected by grafts and those distal to graft insertions. In aortocoronary bypass grafts, 23 subjects (14%) assigned to placebo had new lesions in the follow-up angiogram, compared with 4 subjects (2%) assigned to gemfibrozil ( P Conclusions Gemfibrozil therapy retarded the progression of coronary atherosclerosis and the formation of bypass-graft lesions after coronary bypass surgery in men with low HDL cholesterol as their main lipid abnormality.

Background Coronary risk factors related to the insulin resistance syndrome tend to cluster in the same individual. Our previous studies have shown that the dyslipidemia characteristic of this syndrome—low HDL cholesterol and high triglyceride (TG) levels—responds well to treatment with gemfibrozil. Most factors related to insulin-resistance syndrome decrease fibrinolytic capacity, whereas a recent study showed that gemfibrozil improves it and thus may attenuate thrombotic events. To discover whether subjects with clustering of factors related to this resistance might in particular benefit from gemfibrozil, we reanalyzed the Helsinki Heart Study data. Methods and Results We used Cox regression models to explore the effects of gemfibrozil among overweight subjects with additional coronary risk factors in this hypercholesterolemic male population of 2046 subjects randomized to gemfibrozil and 2035 to placebo. The effect of gemfibrozil was largely confined to overweight subjects: among those with body mass index (BMI) >26 kg/m 2 , the net difference in cardiac end points between gemfibrozil and placebo groups was 21 (25 of 1119 versus 46 of 1081), and in those with BMI ≤26 kg/m 2 , it was 7 (31 of 927 versus 38 of 954). The risk reduction with gemfibrozil was 78% ( P =.002) among those with BMI >26 kg/m 2 and dyslipidemia (TG ≥2.3 mmol/L and HDL cholesterol 26 kg/m 2 and three or four of the following factors present—smoking, sedentary lifestyle, blood pressure ≥140/90 mm Hg, or blood glucose >4.4 mmol/L—the risk reduction was 68% ( P =.03). Conclusions Gemfibrozil reduced the coronary risk mainly in overweight subjects with additional risk factors known to contribute to the insulin-resistance syndrome or predispose to it.

Background There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years’ duration (n=35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention. Methods and Results The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% ( P P P P P P P Conclusions The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.

Background Data concerning the relation between anti-phospholipid (aPL) antibodies and myocardial infarction in subjects without evidence of overt autoimmune disease are conflicting. All published studies have been performed on survivors of myocardial infarction or in patients with established coronary heart disease. The purpose of the present study was to determine whether the presence of aPL antibodies, namely, anti-cardiolipin (aCL) antibodies, carries a risk for myocardial infarction in a prospective cohort. Methods and Results The sera to be studied were drawn at entry from middle-aged dyslipidemic men (non–high-density lipoprotein cholesterol, ≥5.2 mmol/L) participating in the Helsinki Heart Study, a 5-year coronary primary prevention trial with gemfibrozil. Samples were tested for IgG-class antibodies to cardiolipin by an ELISA. The risk was estimated with logistic regression analysis using a nested case-control design with 133 patients (myocardial infarction or cardiac death) and 133 control subjects, matched for treatment (gemfibrozil/placebo) and geographical area. The aCL antibody level, as expressed in optical density units, was significantly higher in patients than in control subjects (0.417 versus 0.361; P r =.40, P Conclusions In a prospective cohort of healthy middle-aged men, the presence of a high aCL antibody level is an independent risk factor for myocardial infarction or cardiac death. Antibodies to cardiolipin and oxidized LDL may, at least in part, represent cross-reactive antibody populations.

BACKGROUND Platelet-associated epidermal growth factor (EGF) and transforming growth factor-beta (TGF-beta) can augment synthesis of plasminogen activator inhibitor type 1 (PAI-1). Accordingly, exacerbation of atherogenesis may accompany release of platelet-associated growth factors (or mitogens) occurring in association with occult, repetitive thrombosis and thrombolysis. In the Helsinki primary prevention trial, gemfibrozil decreased coronary events but did so essentially only in initially hypertriglyceridemic subjects. Such subjects are known to exhibit high concentrations of PAI-1 in plasma. METHODS AND RESULTS To determine whether pharmacological concentrations of gemfibrozil directly affect PAI-1 synthesis, we characterized its effects on a human hepatoma cell line (Hep G2) in vitro. Gemfibrozil decreased basal PAI-1 secretion by 43% and attenuated the augmentation of PAI-1 synthesis over 24 hours induced by EGF and TGF-beta by 37% and 39% without altering overall protein synthesis. Furthermore, it blocked the EGF and TGF-beta-induced increases in PAI-1 mRNA over 6 hours by 65% and 60%. Increases in plasma PAI activity induced by infusion of purified growth factors or by autologous platelet lysates in rabbits were inhibited by gemfibrozil by more than 50%. CONCLUSIONS Beneficial effects of gemfibrozil in reducing coronary events in hypertriglyceridemic patients may depend, in part, on potentiation of fibrinolysis by direct diminution of synthesis of endogenous PAI-1.

BACKGROUND We studied the joint effect of baseline triglyceride and lipoprotein cholesterol levels on the incidence of cardiac end points in the trial group (n = 4,081) of the Helsinki Heart Study, a 5-year randomized coronary primary prevention trial among dyslipidemic middle-aged men. The relative risks (RR) were calculated using Cox proportional hazards models with a dummy variable technique that allows simultaneous study of subgroup combinations from the placebo and treatment groups. METHODS AND RESULTS In the placebo group (n = 2,045), the low density lipoprotein cholesterol (LDL-C)/high density lipoprotein cholesterol (HDL-C) ratio was the best single predictor of cardiac events. This ratio in combination with the serum triglyceride level revealed a high-risk subgroup: subjects with LDL-C/HDL-C ratio greater than 5 and triglycerides greater than 2.3 mmol/l had a RR of 3.8 (95% CI, 2.2-6.6) compared with those with LDL-C/HDL-C ratio less than or equal to 5 and triglyceride concentration less than or equal to 2.3 mmol/l. In subjects with triglyceride concentration greater than 2.3 mmol/l and LDL-C/HDL-C ratio less than or equal to 5, RR was close to unity (1.1), whereas in those with triglyceride level less than or equal to 2.3 mmol/l and LDL-C/HDL-C ratio greater than 5, RR was 1.2. The high-risk group with LDL-C/HDL-C ratio greater than 5 and triglyceride level greater than 2.3 mmol/l profited most from treatment with gemfibrozil, with a 71% lower incidence of coronary heart disease events than the corresponding placebo subgroup. In all other subgroups, the reduction in CHD incidence was substantially smaller. CONCLUSIONS Serum triglyceride concentration has prognostic value, both for assessing coronary heart disease risk and in predicting the effect of gemfibrozil treatment, especially when used in combination with HDL-C and LDL-C.

Background— Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. Methods and Results— This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (−5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. Conclusions— The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

A vast body of epidemiological studies has demonstrated a continuous relationship between serum cholesterol levels and CHD whereby the risk of CHD increases across the entire range of cholesterol values. A 10% reduction in cholesterol level over a period of several decades has been associated with a 30% reduction in CHD incidence, after correction for a number of confounders and adjustments for measurement errors.1 Clinical trials not only have addressed the question whether decreases in cholesterol levels will reduce CHD but have demonstrated how soon such benefits may be observed. Furthermore, comparison of the magnitude of benefit of relatively short-term treatment in the trials (eg, a few years) versus the theoretical maximum of long-term differences predicted from the epidemiological studies (eg, several decades) provides a framework to assess the potential long-term benefits of sustained cholesterol reduction, well beyond the duration of the trials. The first generation of lipid-lowering trials (Helsinki [gemfibrozil],2 WHO [clofibrate],3 LRC-CPPT [cholestyramine]4 ) used drugs that lowered cholesterol only modestly (about 10%); some of these drugs produced side effects, so that compliance with treatment was suboptimal, and the studies were consequently inadequately powered to provide reliable estimation of the effects of lipid lowering on mortality. Although at first glance, the results of these trials appeared to be inconclusive or even contradictory, a comprehensive overview of these trials in an epidemiological context1 provided a coherent result: the gains in CHD reduction were related to the degree of cholesterol lowering and the duration of the intervention. More recently, with the availability of 3-hydroxy-3 methyl glutaryl coenzyme A reductase inhibitors, the degree of cholesterol lowering is about 25%, a substantial effect that is 2.5 times that seen in the first-generation trials with cholestyramine or the fibrates. This large effect, combined with an increased duration of …

Background— Recent evidence suggests that chloride channels may be involved in ischemic preconditioning (IPC). In this study, we tested whether the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels, which are expressed in the heart and activated by protein kinase A and protein kinase C, are important for IPC in isolated heart preparations from wild-type (WT) and CFTR knockout (CFTR −/− ) mice. Methods and Results— Hearts were isolated from age-matched WT or CFTR −/− (B6.129P2-Cftr tm1Unc and STOCKCftr tm1Unc -TgN 1Jaw) mice and perfused in the Langendorff or working-heart mode. All hearts were allowed to stabilize for 10 minutes before they were subjected to 30 or 45 minutes of global ischemia followed by 40 minutes of reperfusion (control group) or 3 cycles of 5 minutes of ischemia and reperfusion (IPC group) before 30 or 45 minutes of global ischemia and 40 minutes of reperfusion. Hemodynamic indices were recorded to evaluate cardiac functions. Release of creatine phosphate kinase (CPK) in the samples of coronary effluent and infarct size of the ventricles were used to estimate myocardial tissue injury. In WT adult hearts, IPC protected cardiac function during reperfusion and significantly decreased ischemia-induced CPK release and infarct size. A selective CFTR channel blocker, gemfibrozil, abrogated the protective effect of IPC. Furthermore, targeted inactivation of the CFTR gene in 2 different strains of CFTR −/− mice also prevented IPC’s protection of cardiac function and myocardial injury against sustained ischemia. Conclusions— CFTR Cl − channels may serve as novel and crucial mediators in mouse heart IPC.

Statin monotherapy is generally well tolerated, with a low frequency of adverse events. The most important adverse effects associated with statins are myopathy and an asymptomatic increase in hepatic transaminases, both of which occur infrequently. Because statins are prescribed on a long-term basis, however, possible interactions with other drugs deserve particular attention, as many patients will typically receive pharmacological therapy for concomitant conditions during the course of statin treatment. This review summarizes the pharmacokinetic properties of statins and emphasizes their clinically relevant drug interactions.

Most young and middle-aged persons who develop coronary heart disease (CHD) have some form of dyslipidemia with mild to moderate increases in plasma cholesterol or triglyceride concentrations (or both), often accompanied by reduced concentrations of HDL cholesterol. In such patients, treatment with diet or drugs directed mainly at lowering the concentration of atherogenic lipoproteins reduces the progression of coronary artery atherosclerotic disease and associated clinical events and prolongs life.1 Although many patients with CHD have abnormalities affecting all of the major lipoprotein classes (VLDL, LDL, and HDL), in some only a single class is affected. Low HDL cholesterol is a powerful risk factor for CHD, even when total cholesterol concentrations are normal.2 Although low HDL cholesterol is usually accompanied by increased VLDL cholesterol and triglyceride concentrations in populations (but not by high concentrations of LDL cholesterol),3 isolated low HDL cholesterol is frequent in CHD patients.4 How to manage patients with isolated low HDL cholesterol, particularly those with manifest atherosclerotic vascular disease, is unclear. Increased physical activity and judicious use of alcoholic beverages can increase HDL cholesterol, usually modestly. Drugs that increase HDL cholesterol generally lower atherogenic lipoprotein concentrations as well, and the benefit of such drug use is generally ascribed primarily to reduced concentrations of these lipoproteins, especially LDL. However, recent observational studies and some clinical trials have placed increased emphasis on changes in components of VLDL as determinants of the progression of coronary artery atherosclerosis, assessed angiographically. For example, in the …

Studies have shown that treatment of hyperlipidemia, especially lowering of plasma LDL levels, retards the progression of coronary atherosclerosis and prevents clinical cardiovascular events. No such studies have focused on subjects with low levels of HDL cholesterol.We randomly assigned 395 post-coronary bypass men, who had an HDL cholesterol concentrationor = 1.1 mmol/L and LDL cholesterolor = 4.5 mmol/L, to receive gemfibrozil 1200 mg/d or placebo. Coronary angiography was performed at baseline and after, on average, 32 months of therapy. Changes in coronary dimensions were assessed by computer-assisted analysis. Average on-trial serum triglyceride concentrations were 1.69+/-0.68 and 1.02+/-0.37, total cholesterol 5.48+/-0.68 and 4.83+/-0.63, LDL cholesterol 3.84+/-0.59 and 3.39+/-0.56, and HDL cholesterol 0.88+/-0.15 and 0.98+/-0.17 mmol/L in the placebo and gemfibrozil groups, respectively (mean+/-SD, each P.001). The change in per-patient means of average diameters of native coronary segments was -0.04+/-0.11 mm in the placebo group and -0.01+/-0.10 mm in the gemfibrozil group (P=.009). The equivalent changes in minimum luminal diameters of stenoses were -0.09+/-0.18 and -0.04+/-0.15 mm, respectively (P=.002). A similar, albeit nonsignificant, trend toward treatment benefit was found in the predefined primary study end point, segments unaffected by grafts and those distal to graft insertions. In aortocoronary bypass grafts, 23 subjects (14%) assigned to placebo had new lesions in the follow-up angiogram, compared with 4 subjects (2%) assigned to gemfibrozil (P.001).Gemfibrozil therapy retarded the progression of coronary atherosclerosis and the formation of bypass-graft lesions after coronary bypass surgery in men with low HDL cholesterol as their main lipid abnormality.

Background Insulin and its precursors found in increased plasma concentrations in non–insulin-dependent diabetes mellitus (NIDDM) augment synthesis of plasminogen activator inhibitor type 1 (PAI-1) in Hep G2 cells in vitro and in rabbit liver in vivo. Reduced endogenous fibrinolysis secondary to increased PAI-1 activity may exacerbate atherogenesis. Recently, the reduction of the coronary heart disease incidence in the Helsinki Heart Study has implicated favorable modulation of endogenous fibrinolysis by gemfibrozil. Methods and Results In Hep G2 cells, 500 (700) μmol/L gemfibrozil decreased basal secretion of PAI-1 by 26% (43%) ( P =.012 and P =.021, respectively) and attenuated insulin-induced (10 nmol/L) augmentation of PAI-1 in conditioned media by 61% (109%) ( P =.010) within 24 hours. Inhibition was dependent on the duration of exposure (0 to 48 hours) and on the concentration of gemfibrozil (0 to 700 μmol/L) but not on the concentration of insulin (0.1 to 100 nmol/L). Gemfibrozil attenuated the augmentation of PAI-1 secretion induced by proinsulin (>100%), by des(31,32)proinsulin (75%), and by des(64,65)proinsulin (77%) as well (10 nmol/L each). The specificity of these effects was confirmed by the unaltered levels of newly synthesized protein (metabolic labeling) and of total protein (both in conditioned media and cell lysates). Secretion of fibrinogen by Hep G2 cells was not affected by gemfibrozil. Changes in PAI-1 protein levels reflected modulation of PAI-1 gene expression as manifested by changes in levels of 3.2-kb PAI-1 mRNA (Northern blots). Conclusions Gemfibrozil attenuated the augmentation of synthesis and secretion of PAI-1 induced by insulin and its precursors directly and specifically. Accordingly, gemfibrozil may exert favorable therapeutic effects normalizing impaired fibrinolysis in patients with hyperinsulinemia such as NIDDM.

Background Plasminogen activator inhibitor type 1 (PAI-1), the primary physiological inhibitor of endogenous plasminogen activators, has been implicated as a potentiating factor in atherogenesis as well as in coronary thrombosis. We and others have observed attenuation of PAI-1 expression by gemfibrozil both in vivo and in vitro. Methods and Results To determine whether other lipid-lowering agents with different mechanisms of action exert similar effects, we exposed Hep G2 cells, a highly differentiated human hepatoma cell line, to selected concentrations of niacin. Accumulation of PAI-1 protein, assayed with an ELISA, decreased in conditioned media by 72% in 48 hours in a specific, concentration-dependent fashion. Metabolic labeling experiments demonstrated a decrease in the rate of PAI-1 synthesis. Northern blot analysis demonstrated a preceding, parallel, and specific decrease in the concentration of PAI-1 mRNA. Niacin attenuated the increased PAI-1 synthesis induced by mediators released from thrombi as well. Thus, with 4.25 ng/mL transforming growth factor-β 1 , PAI-1 accumulation increased 4.5-fold in conditioned media in 48 hours. However, niacin attenuated the increase by 65%. Again, both the rate of PAI-1 synthesis and PAI-1 mRNA were reduced. The increased plasma PAI-1 activity and PAI-1 mRNA in liver induced by dexamethasone (0.8 mg IP) in vivo in rats were attenuated by 3 weeks of pretreatment with niacin. Conclusions These results suggest that niacin, by decreasing PAI-1 expression, may potentiate fibrinolysis, thereby decreasing the stimulation of atherogenesis by clot-associated mitogens associated with microthrombi. Furthermore, the results imply that a pathogenetic link may exist between intracellular lipid metabolism and regulation of expression of fibrinolytic system components.

I recall first learning of the importance of cholesterol from the work of Dr Ancel Keys, based on his landmark epidemiological studies subsequently identified as the Seven Countries Study.1 These population-based studies, in my own mind years ago, provided a general reference for judging the prevalence of coronary artery disease while providing a marker for risk of coronary artery disease over the long term. Most practitioners did not think of potential benefits to individual patients based on any short-term lowering of cholesterol levels, and treatment options were limited until the introduction of gemfibrozil and the statin drugs. The article by Andrews and colleagues2 in this issue of Circulation reflects how dramatically our understanding has changed regarding the consequences of elevated total and LDL cholesterol levels and the opportunities to intervene with effective treatment strategies. In this study, selected patients with documented coronary artery disease associated with myocardial ischemia on ambulatory ECG monitoring were randomized to an American Heart Association step 1 diet plus lovastatin or the diet plus a placebo. Four to 6 months after randomization, lower mean total and LDL cholesterol levels were found in those randomized to lovastatin therapy. The 25% reduction in LDL in the lovastatin group was associated with a “highly significant” reduction in myocardial ischemia compared with the control group, based on quantification of myocardial ischemia by 24-hour ECG monitoring. The authors appropriately conclude that “cholesterol lowering with lovastatin appears to be effective in eliminating myocardial ischemia during …

A basic difference between dietary and drug therapy of hypercholesterolemia is that dietary therapy can be used as part of a population strategy, whereas the decision to use drugs is always made on an individual basis. In each case, the decision to treat must be based on the assumption that more good than harm is caused to the patient. This is a difficult situation for the physician. As long as there is no easy way of assessing the state and rate of progression of coronary lesions, the physician must treat the patient on statistical grounds only, i.e., rely on the results of studies showing that lowering serum cholesterol significantly decreases the risk of coronary events. Such evidence has recently been strengthened, which increases motivation for both physician and patients. The current general opinion is that drug therapy must be generally confined to those at high risk, i.e., patients with severe hypercholesterolemia. For individuals with moderately elevated serum cholesterol levels, dietary advice and correction of other risk factors should be adequate.

We investigated the hypocholesterolemic effects of lovastatin alone and in combination with gemfibrozil on plasma lipids and lipoproteins in 12 adult patients with well-characterized heterozygous familial hypercholesterolemia. Plasma concentrations of low density lipoprotein (LDL) cholesterol decreased from 321 +/- 14 mg/dl on diet only to 207 +/- 8 mg/dl (-35.5%) on single-drug therapy with lovastatin at a dose of 40 mg twice daily, whereas triglyceride concentrations fell by 27.6% (from 145 +/- 20 to 105 +/- 20 mg/dl). Subsequent addition of gemfibrozil at a dose of 600 mg twice daily resulted in a nonsignificant further reduction in LDL cholesterol to 194 +/- 7 mg/dl (-39.6% change from baseline), whereas triglycerides decreased to 80 mg/dl (-44.8%, p less than 0.05 vs. single-drug therapy with lovastatin). Plasma concentrations of high density lipoprotein (HDL) increased slightly during lovastatin and combined drug therapy (from 45 +/- 4 mg/dl at baseline to 46 +/- 4 mg/dl on lovastatin to 48 +/- 4 mg/dl on lovastatin plus gemfibrozil). The response to combination drug therapy in individual patients was heterogeneous and clinically significant decreases in LDL cholesterol concentrations were noted in two of the 12 patients, whereas in three patients LDL cholesterol concentrations increased on the combined drug regimen. One patient developed an asymptomatic increase in creatine kinase on monotherapy with lovastatin and a more pronounced and symptomatic increase during combination drug therapy with lovastatin plus gemfibrozil.(ABSTRACT TRUNCATED AT 250 WORDS)