M. Heikki Frick

Prevention of the Angiographic Progression of Coronary and Vein-Graft Atherosclerosis by Gemfibrozil After Coronary Bypass Surgery in Men With Low Levels of HDL Cholesterol

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 < or = 1.1 mmol/L and LDL cholesterol < or = 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). 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.

Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants

To prospectively assess the role of lipoprotein(a) (Lp(a)) as a risk factor for coronary heart disease, the serum Lp(a) concentration was determined in 130 subjects without coronary events and in 138 patients in whom coronary events (i.e. fatal and non-fatal myocardial infarction and cardiac death) occurred during the 5-year Helsinki Heart Study. The participants of this study (n = 4081) were 40-55-year-old men who were devoid of coronary heart disease at the beginning of the trial; half were randomized to gemfibrozil and the other half to placebo treatment. In patients with coronary events blood pressure and total cholesterol were not significant predictors of the events but their LDL cholesterol was higher than compared to the control group in this cohort (P less than 0.05). The serum Lp(a) concentration was determined by immunoassay from samples obtained 3 months after the beginning of the trial and then stored at -20 degrees C until analysed. Studies on the effect of long term storage at -20 degrees C on serum Lp(a) levels did not reveal significant changes in Lp(a) concentration in sera stored for up to 8.5 years. The distribution of Lp(a) concentrations were similar in the men with coronary events and the controls. Nor did the mean or median levels of Lp(a) differ significantly between the two groups. Measurements of Lp(a) levels in fresh samples using 2 different immunoassays did not reveal any significant difference between the participants who had survived a myocardial infarction or participants without cardiac events. Thus, we conclude that in the Helsinki Heart Study cohort the serum Lp(a) level was not a predictor of future coronary events.

Heart Rate Variability and Progression of Coronary Atherosclerosis

Low heart rate (HR) variability is associated with increased risk of cardiovascular morbidity and mortality, but the causes and mechanisms of this association are not well known. This prospective study was designed to test the hypothesis that reduced HR variability is related to progression of coronary atherosclerosis. Average HR and HR variability were analyzed in 12-hour ambulatory ECG recordings from 265 qualified patients participating in a multicenter study to evaluate the angiographic progression of coronary artery disease in patients with prior coronary artery bypass surgery and low high-density lipoprotein cholesterol concentrations (<1.1 mmol/L). Participants were randomized to receive a placebo or gemfibrozil therapy. The progression of coronary atherosclerosis was estimated by quantitative, computer-assisted analysis of coronary artery stenoses from the baseline angiograms and from repeated angiograms performed an average of 32 months later. The progression of focal coronary atherosclerosis of the patients randomized to placebo therapy was more marked in the tertile with the lowest standard deviation of all normal to normal R-R intervals (SDNN, 74+/-13 ms; mean decrease in the per-patient minimum luminal diameter -0.17 mm; 95% confidence interval [CI], -0.23 to -0.12 mm) than in the middle tertile (SDNN, 107+/-7 ms; mean decrease -0.05 mm; 95% CI, -0.08 to -0.01 mm) or highest tertile (SDNN, 145+/-25 ms; mean change 0.01 mm; 95% CI, -0. 04 to 0.02 mm) (P<0.001 between the tertiles). This association was abolished by gemfibrozil. SDNN was lower (P<0.001) and minimum HR was faster (P<0.01) in the patients with marked progression than in those with regression of focal coronary atherosclerosis. In multiple regression analysis including HR variability, minimum HR, demographic and clinical variables, smoking, blood pressure, glucose, lipid measurements and lipid-modifying therapy, progression of focal coronary atherosclerosis was independently predicted by the SDNN (beta=0.24; P=0.0001). Low HR variability analyzed from ambulatory ECG predicts rapid progression of coronary artery disease. HR variability provided information on progression of focal coronary atherosclerosis beyond that obtained by traditional risk markers of atherosclerosis.

Peroxisome Proliferator-Activated Receptor α Gene Variants Influence Progression of Coronary Atherosclerosis and Risk of Coronary Artery Disease

BACKGROUND Peroxisome proliferator-activated receptor alpha (PPARalpha) 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 PPARalpha 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 PPARalpha gene affects progression of atherosclerosis and risk of IHD. Absence of association with plasma lipid concentrations suggests that PPARalpha affects atherosclerotic progression directly in the vessel wall.

APOA5 gene variants, lipoprotein particle distribution, and progression of coronary heart disease results from the LOCAT study

Animal and human studies support a role for apolipoprotein A-V (apoA-V) in triglyceride (TG) metabolism. We examined the relationship of APOA5 −1131T>C and S19W with lipid subfractions and progression of atherosclerosis in the Lopid Coronary Angiography Trial. Compared with −1131TT men (n = 242), carriers of the −1131C allele (n = 54) had significantly higher total TG (P = 0.03), reflected in significantly increased VLDL mass [higher VLDL-TG, VLDL-cholesterol, VLDL-protein, and surface lipids (all P < 0.05)]. Because apoB levels were unaffected by genotype, this suggests an increase in VLDL size and not number. Compared with 19SS men (n = 268), 19W carriers (n = 44) had higher intermediate density lipoprotein (IDL)-TG, IDL-cholesterol (P = 0.04), and IDL-surface components [free cholesterol (P = 0.005) and phospholipids (P = 0.017)] but not protein content, suggesting an increase in IDL lipid enrichment resulting in an increase in IDL size. 19W carriers also showed a trend toward increased progression of atherogenesis, as measured by change in average diameter of segments (−0.46 ± 0.011 mm compared with −0.016 ± 0.006 mm) in 19SS men (P = 0.08). There was no effect of genotype on the response of these parameters to gemfibrozil treatment. These results shed new light on the role of APOA5 variants in TG metabolism and coronary heart disease risk.

The 5A/6A polymorphism in the promoter of the stromelysin-1 (MMP-3) gene predicts progression of angiographically determined coronary artery disease in men in the LOCAT gemfibrozil study

The relationship between the 5A/6A stromelysin-1 promoter polymorphism and progression of angiographically determined coronary artery disease (CAD) has been examined in men treated for 32 months with gemfibrozil or placebo in the Lopid Coronary Angiography Trial (LOCAT). The frequency of the 5A allele was 0.40 (95%, CI, 0.36-0.43), and in the sample as a whole 12% of the men were homozygous for the 5A allele. In the placebo group, diffuse progression of disease was, on average, completely prevented in men with the genotype 5A/5A as measured by a 0.30% increase in mean average diameter of the coronary artery segments (ADS), compared with a mean 1.79% decrease in the combined group with the genotype 5A6A or 6A6A (mean +/- S.E.M., +0.007 +/- 0.020 mm vs. -0.043 +/- 0.0.08 mm, P = 0.03). A similar relationship with genotype was seen for disease progression determined by the mean minimal luminal diameter (MLD); with the 5A5A group decreasing by an average of 1.72% compared with 5.54% in the 5A/6A plus 6A/6A group (-0.029 +/- 0.034 mm vs. -0.102 +/- 0.013 mm, P = 0.06). In the gemfibrozil-treated group, the effect on disease progression associated with the 5A/6A alleles was of a similar pattern as in the placebo group, but the effect was less marked and was not statistically significant. This study confirms the previously reported beneficial effect on disease progression associated with the 5A allele and raises the possibility that patients with CAD who are homozygous for the 6A allele, and who represent 25-30% of the population, may be at particular risk of rapid progression of disease and may require particularly aggressive lipid lowering therapy to prevent disease progression.

The Helsinki Heart Study: Central Findings and Clinical Implications

This paper describes the central findings and discusses the clinical implications of the Helsinki Heart Study. This was a controlled primary prevention trial to test the hypothesis that using gemfibrozil to lower the concentrations of serum low density lipoprotein (LDL) and very low density lipoprotein (VLDL) and to raise that of high density lipoprotein (HDL) protects subjects against coronary heart disease.

Associations Between Lipoproteins and the Progression of Coronary and Vein-Graft Atherosclerosis in a Controlled Trial With Gemfibrozil in Men With Low Baseline Levels of HDL Cholesterol

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; HDL2 cholesterol, 0.41; and HDL3 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. HDL3 but not HDL2 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 HDL3 was protective in this group of men selected for their low initial HDL levels.

Progression of Atherosclerosis Is Associated With Variation in the α1-Antitrypsin Gene

Objective—&agr;1-Antitrypsin (AAT) protects elastic tissue and may play a role in atherogenesis. The association of atherosclerosis progression with common AAT variants was considered in 2 clinical trials. Methods and Results—We examined the association of AAT V213A, S and Z deficiency alleles, and the functional 3′ UTR 11478G>A with change in minimal luminal diameter, a measure of focal disease, in the Lopid Coronary Angiography Trial gemfibrozil study of post-bypass men. S or Z carriers (n=14) showed strong progression of disease on placebo (11.5%) but responded well to treatment (3% regression). 11478A carriers treated with placebo or gemfibrozil showed significantly more disease progression (n=8, −14.5% and n=16, −4.0%, respectively) than 11478GG men (n=107, −7.0% and n=108, −1.4%, respectively; overall, P =0.003). VV213 men treated with gemfibrozil (n=68) showed −4.8% progression, whereas A213 carriers (n=55) showed +1.4% regression of disease (P =0.001). No V213A effect was seen on placebo (P =0.11). In the Diabetes Atherosclerosis Intervention Study fenofibrate trial of angiographic progression in type 2 diabetes, the association of 11478A with increased disease progression was confirmed in the treatment group, but not the gemfibrozil-treated A213 association with regression, suggesting a pharmacogenetic difference. Conclusions—Disease progression is associated with variation in AAT, and low AAT levels promote atherogenesis.

Remnant-like lipoprotein particle cholesterol concentration and progression of coronary and vein-graft atherosclerosis in response to gemfibrozil treatment

Remnant lipoproteins such as chylomicron and very low density lipoprotein (VLDL) remnants have been implicated in the progression of coronary atherosclerosis. Recently, a novel method for the determination of the remnant-like lipoprotein particle cholesterol (RLP-C) concentration was developed based on immunoaffinity-separation of plasma. The compositional characteristics of RLP are strikingly similar to those of postprandially modified VLDL. In addition, the method also detects chylomicron remnants. We investigated the relationship between the plasma RLP-C concentration and the angiographic outcome of the 2-year, randomised, placebo-controlled Lipid Coronary Angiography Trial (LOCAT), which used gemfibrozil as lipid lowering agent. The RLP-C response to gemfibrozil treatment has not been described before. Gemfibrozil reduced the median RLP-C concentration by 34%. The on-treatment RLP-C concentration was significantly associated with the progression of the minimum lumen diameter (MLD) (P<0.004). The plasma levels of RLP-C as well as the change in response to treatment was closely associated with plasma triglycerides and the association between on-treatment RLP-C concentration and progression of MLD was not independent of plasma triglycerides. A significant relation was seen between RLP-C and the occurrence of new lesions in vein grafts. Subjects with one new lesion had an approximately 25% higher on-treatment RLP-C concentration and the four patients showing two new lesions had a 100% higher RLP-C concentration than patients without vein graft stenosis. A total of 19 out of 23 subjects having one new lesion, and all four patients showing two new lesions, were assigned to the placebo group. We conclude that the RLP-C concentration, which is likely to reflect the plasma cholesterol contained in postprandially modified VLDL and chylomicron remnants, is strongly associated with angiographically verified progression of focal coronary atherosclerosis, and that lowering of RLPs prevents vein graft stenosis.