H. Robert Superko

Changes in plasma lipids and lipoproteins in overweight men during weight loss through dieting as compared with exercise.

We studied separately the influence of two methods for losing fat weight on the levels of plasma lipids and lipoproteins in overweight sedentary men--decreasing energy intake without increasing exercise (diet), and increasing energy expenditure without altering energy intake (exercise, primarily running)--in a one-year randomized controlled trial. As compared with controls (n = 42), dieters (n = 42) had significant loss of total body weight (-7.8 +/- 0.9 kg [mean +/- SE]), fat weight (-5.6 +/- 0.8 kg), and lean (non-fat) weight (-2.1 +/- 0.5 kg) (P less than 0.001 for each variable), and exercisers (n = 47) had significant loss of total body weight (-4.6 +/- 0.8 kg) and fat weight (-3.8 +/- 0.7 kg) (P less than 0.001 for both variables) but not lean weight (-0.7 +/- 0.4 kg). Fat-weight loss did not differ significantly between dieters and exercisers. All subjects were discouraged from altering their diet composition; however, dieters and exercisers had slight reductions in the percentage of kilojoules derived from fat. As compared with the control group, both weight-loss groups had significant increases (P less than 0.01) in plasma concentrations of high-density lipoprotein (HDL) cholesterol (diet vs. exercise, 0.13 +/- 0.03 vs. 0.12 +/- 0.03 mmol per liter), HDL2 cholesterol (0.07 +/- 0.02 vs. 0.07 +/- 0.02 mmol per liter), and HDL3 cholesterol (0.07 +/- 0.02 vs. 0.06 +/- 0.02 mmol per liter) and significant decreases (P less than 0.05) in triglyceride levels (diet vs. exercise, -0.35 +/- 0.14 vs. -0.24 +/- 0.12 mmol per liter). Levels of total and low-density lipoprotein cholesterol were not significantly changed, relative to values in controls. None of these changes were significantly different between dieters and exercisers. Thus, we conclude that fat loss through dieting or exercising produces comparable and favorable changes in plasma lipoprotein concentrations.

Smallest LDL Particles Are Most Strongly Related to Coronary Disease Progression in Men

Objective—LDLs include particle subclasses that have different mobilities on polyacrylamide gradient gels: LDL-I (27.2 to 28.5 nm), LDL-IIa (26.5 to 27.2 nm), LDL-IIb (25.6 to 26.5 nm), LDL-IIIa (24.7 to 25.6 nm), LDL-IIIb (24.2 to 24.7 nm), LDL-IVa (23.3 to 24.2 nm), and LDL-IVb (22.0 to 23.3 nm in diameter). We hypothesized that the association between smaller LDL particles and coronary artery disease (CAD) risk might involve specific LDL subclasses. Methods and Results—Average 4-year onstudy lipoprotein measurements were compared with annualized rates of stenosis change from baseline to 4 years in 117 men with CAD. The percentages of total LDL and HDL occurring within individual subclasses were measured by gradient gel electrophoresis. Annual rate of stenosis change was related concordantly to onstudy averages of total cholesterol (P =0.04), triglycerides (P =0.05), VLDL mass (P =0.03), total/HDL cholesterol ratio (P =0.04), LDL-IVb (P =0.01), and HDL3a (P =0.02) and inversely to HDL2-mass (P =0.02) and HDL2b (P =0.03). The average annual rate in stenosis change was 6-fold more rapid in the fourth quartile of LDL-IVb (≥5.2%) than in the first quartile (<2.5%, P =0.03). Stepwise multiple regression analysis showed that LDL-IVb was the single best predictor of stenosis change. Conclusions—LDL-IVb was the single best lipoprotein predictor of increased stenosis, an unexpected result, given that LDL-IVb represents only a minor fraction of total LDL.

Advanced Lipoprotein Testing and Subfractionation Are Clinically Useful

Advanced lipoprotein testing and subfractionation have been used for scientific medical investigations in humans for >50 years. Original work from the Framingham Heart Study and the Lawrence Livermore Study, which was conducted at the University of California, first suggested the clinical utility of such advanced testing and provided the groundwork for future research. In the subsequent >50 years, clinical trials have documented that aspects of these tests contribute insight into the atherogenic process that is independent of standard lipid test results. Multiple lifestyle and pharmacological treatment studies have been conducted that reveal significant differences in response to treatment based on lipoprotein subclass classification. These changes in lipoprotein subclass distribution have been linked to differences in arteriographic outcome. Standard tests of low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) misidentify coronary heart disease (CHD) risk status in a substantial portion of the population. Tests of apolipoprotein concentrations are superior to standard LDL-C tests, and it can be argued that they should replace standard lipoprotein cholesterol testing. Advanced lipoprotein tests that were previously available only from university research laboratories are now provided by several commercial laboratories. Although clinical utility has been demonstrated, on the basis of research laboratory quality tests, caution is advised relative to quality control issues and commercial laboratory testing. Response by Mora on p 2395 Over the past 2 decades, evidence has revealed that standard lipoprotein measurements of triglycerides, total cholesterol, LDL-C, and HDL-C fail to identify many lipoprotein abnormalities that contribute to CHD and peripheral vascular disease risk.1 Advanced lipoprotein tests (ALTs) lend insight into subtle yet important aspects of lipoproteins and atherosclerosis that help to explain the relative failure of the LDL-C–lowering strategy to stem the epidemic of atherosclerosis.2 ALTs can be utilized in 4 basic ways: (1) to enhance the accuracy of atherosclerosis …

Effects of solid and liquid guar gum on plasma cholesterol and triglyceride concentrations in moderate hypercholesterolemia

Guar gum is a dietary fiber reported to decrease plasma cholesterol concentration. This study investigated the effect of guar therapy in 50 men with moderately elevated plasma cholesterol who were randomized to an 8-week study of guar therapy. Three forms of guar gum were used: a medium viscosity solid or liquid form, a high viscosity liquid form or placebo. When the medium viscosity guar therapy groups were combined, 4 weeks of therapy were shown to result in a substantial reduction in total and low density lipoprotein (LDL) cholesterol of 25 mg/dl and 23 mg/dl (p = 0.035 and 0.12), respectively. The high viscosity guar group had a reduction in total cholesterol and LDL cholesterol of 37 and 30 mg/dl, respectively (p less than 0.003 and p less than 0.02). Following 8 weeks of therapy, a return toward baseline values was observed. No significant changes were demonstrated in blood chemistries, triglyceride values, total high density lipoprotein (HDL) cholesterol or the HDL2 fraction of HDL cholesterol. The effect of the solid and liquid forms of guar on plasma cholesterol reduction was similar. This study shows that a nonpharmacologic dietary additive reduces plasma total and LDL cholesterol.

Omega-3 Fatty Acid Blood Levels Clinical Significance and Controversy

The relationship of fish and dietary omega-3 fatty acids and cardiovascular disease (CVD) has been investigated in numerous studies and comprehensive reviews and recommendations exist, but guidance on blood concentrations is missing.1–4 Some prospective fish oil treatment investigations report a significant reduction in CVD events but others do not.5–7 A recent meta-analysis did not find a statistically significant relationship between omega-3 consumption and CVD mortality, but it failed to take into account the implications of variability in individual blood levels of omega-3 fatty acids.8 Blood levels of omega-3 fatty acids can be influenced by dietary intake of omega-3 fatty acids and intake with oral supplements. The Multiple Risk Factor Intervention Trial reported in 1995 that serum omega-3 fatty acids blood levels were inversely correlated with coronary heart disease (CHD).9 An association of dietary sources of nonfried fish and blood levels of eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) were reported in the Atherosclerosis Risk In Communities (ARIC) investigation and the Multi-Ethnic Study of Atherosclerosis (MESA) investigations.10,11 Blood levels of dietary omega-3 fatty acids can vary based on geography and diet habits. For example, Japanese living in Japan have higher blood omega-3 fatty acid levels than whites living in Pennsylvania and Japanese Americans living in Honolulu. The lower 5th percentile of blood omega-3 fatty acids in the Japanese living in Japan is higher than the mean levels in whites and Japanese Americans even though total fat is comparable.12 The purpose of this review is to explore insight derived from clinical investigations reporting blood or plasma levels of omega-3 fatty acids and the relationship to CHD risk that may shed light on the fish oil controversy. A National Library of Medicine PubMed search was conducted with the key words omega-3, …

Lipoprotein and hepatic lipase activity and high-density lipoprotein subclasses after cardiac transplantation

Atherosclerosis is the leading obstacle to long-term survival in cardiac transplant patients. Increases in plasma triglycerides and lipoprotein cholesterol levels occur after transplantation that may contribute to transplant atherosclerosis. The etiology of this increase is unclear. We investigated the interaction of immunosuppressive medications with plasma triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, the HDL subclasses HDL2 and HDL3 cholesterol, and hepatic and lipoprotein lipase activity in 72 consecutive cardiac transplant patients compared to 51 healthy control subjects. In the transplantation group, greater concentrations of plasma triglyceride (80%, p less than 0.001), LDL cholesterol (16%, p less than 0.005) and hepatic lipase activity (100%, p less than 0.001) were noted, whereas lipoprotein lipase activity was noted to be significantly lower (124%, p less than 0.001). No difference was detected in HDL, HDL2, or HDL3 cholesterol. Cyclosporine dose was significantly associated with hepatic lipase activity (r = 0.33, p less than 0.02) and inversely associated with lipoprotein lipase activity (r = -0.28, p less than 0.05). Lipoprotein lipase activity after transplantation correlated inversely with triglycerides (r = -0.36, p less than 0.002) and positively with HDL cholesterol (r = 0.23, p less than 0.05) and HDL2 cholesterol (r = 0.29, p less than 0.05). Hepatic lipase activity correlated inversely with LDL cholesterol (r = -0.21, p less than 0.08). In multiple regression analysis, cyclosporine dose was the major source of variation in hepatic lipase activity.

Effectiveness of low-dose colestipol therapy in patients with moderate hypercholesterolemia☆

Recommended doses of bile-acid binding resins have an established hypocholesterolemic effect, but data on responses to low doses, especially in women and subjects with moderate hypercholesterolemia, are sparse. A double-blind, placebo-controlled, randomized trial of 3 low doses of colestipol hydrochloride was conducted in women and men with moderate hypercholesterolemia. Men and women with plasma low-density lipoprotein (LDL) cholesterol concentrations greater than 4 mmol/liter (155 mg/dl) and triglyceride concentrations less than 2.82 mmol/liter (250 mg/dl) were recruited for the study. Eligible patients (54 women and 98 men) were placed on the American Heart Association step I diet 6 weeks before randomization. Participants were subsequently assigned to 1 of 4 drug treatment groups (placebo, and 5, 10 and 15 g/day of colestipol in 2 divided doses) for an additional 12 weeks. Of the 152 patients randomized, 141 completed all aspects of the study. For the treatment groups--placebo, and 5, 10 and 15 g of colestipol--LDL cholesterol reductions (mmol/liter) were observed respectively (n = 141): 0.10 +/- 0.49 (2.7%), 0.65 +/- 0.41 (16.3%), 0.98 +/- 0.36 (22.8%) and 1.17 +/- 0.47 (27.2%) (p less than 0.001). Similar changes were observed in total cholesterol and apolipoprotein B concentrations. The apolipoprotein B/LDL cholesterol ratio increased significantly with increasing colestipol dosage. Modest but insignificant changes in plasma triglyceride levels occurred, and high-density lipoprotein cholesterol levels remained unchanged. A dose of 5 g/day of colestipol achieved 51% of the LDL cholesterol reduction noted with 15 g/day. Low-dose colestipol therapy is effective in the treatment of patients with moderate hypercholesterolemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of cessation of caffeinated-coffee consumption on ambulatory and resting blood pressure in men☆

Coffee consumption has been weakly linked to high blood pressure (BP). The hypothesis that cessation of caffeinated-coffee consumption lowers ambulatory BP was tested in men in a randomized trial. One hundred eighty-six middle-aged, normotensive, male, habitual caffeinated-coffee consumers were recruited. Of these subjects, 150 had sufficiently complete, ambulatory BP measurements for analysis. After 2 months of standard caffeinated-coffee consumption, subjects were randomized to consume an equal amount of the same standard caffeinated coffee or a standard decaffeinated coffee, or to discontinue coffee consumption for 2 months. Diet composition, body weight and exercise did not change. Resting BP and heart rate were not different between the groups before and after intervention. In comparison with the continued caffeinated-coffee group (control), the decaffeinated-coffee group revealed significant reductions in mean ambulatory systolic BP during the morning (-4.0 +/- 11 mm Hg; p = 0.014), afternoon (-5.3 +/- 10 mm Hg; p = 0.001) and evening (-3.2 +/- 10 mm Hg; p = 0.003) hours, reductions in mean ambulatory diastolic BP during the afternoon (-1.8 +/- 10 mm Hg; p = 0.063) and evening (-1.8 +/- 10 mm Hg; p = 0.059) hours and no change in ambulatory heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug therapy and the prevention of atherosclerosis in humans

The results of the World Health Organization Cooperative Trial, the Coronary Drug Project, the Coronary Primary Prevention Trial and the Helsinki Heart Study indicate that clinical expression of coronary artery disease can be delayed with pharmacologic modification of plasma lipoproteins. Change in coronary artery disease can be semiquantitated by repeat arteriograms. Three randomized clinical trials indicate that rate of progression of atherosclerosis, as defined by arteriography, can be reduced, and existing lumen obstruction decreased. Tendon xanthomas occur in hypercholesterolemia, and reduction in xanthoma size with drug therapy suggests an improved atherosclerotic disease state. The clinician has a variety of pharmacologic therapies available. The role of bile acid-binding resins, fibric acid derivatives, hydroxymethylglutaryl coenzyme A reductase inhibitors, nicotinic acid and antioxidants is each unique. Understanding the role of lipoproteins in atherosclerosis will help in selecting the most appropriate therapy for each individual patient. Medications not designed for their lipoprotein effects can significantly alter lipoproteins. Medications, such as nonselective beta blockers, can alter low-density lipoprotein (LDL) subclass distribution with no change in LDL cholesterol content. Such changes may eradicate part of the beneficial cardiovascular effect of beta blockade therapy. In the future, therapeutic choices may depend in part on lipoprotein abnormalities such as lipoprotein (a), apolipoprotein E isoforms, hyperapobetalipoproteinemia, LDL.

Atherogenic Lipoprotein Subfractions Determined by Ion Mobility and First Cardiovascular Events After Random Allocation to High-Intensity Statin or Placebo: The JUPITER Trial

Background —Cardiovascular disease (CVD) can occur in individuals with low LDL-cholesterol (LDL-c). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-c and high C-reactive protein that was randomized to high-intensity statin or placebo. Methods and Results —In 11,186 JUPITER participants, we tested whether lipids, apolipoproteins, and ion mobility (IM)-measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-c was not associated with CVD (adjusted HR per SD, 1.03, 95% CI 0.88-1.21). In contrast, associations with CVD events were observed for baseline non-HDL-cholesterol (non-HDL-c: 1.18, 1.01-1.38), apolipoprotein B (apoB: 1.28, 1.11-1.48), and IM-measured non-HDL particles (non-HDL-p: 1.19, 1.05-1.35) and LDL particles (LDL-p: 1.21, 1.07-1.37). Association with CVD events was also observed for several LDL and VLDL subfractions, but not for IM-measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-c, non-HDL-c, and apoB; these were also associated with CVD/all-cause death, as were several LDL and VLDL subfractions albeit with a pattern of association that differed from the baseline risk. Conclusions —In JUPITER, baseline LDL-c was not associated with CVD events, in contrast with significant associations for non-HDL-c and atherogenic particles: apoB and IM-measured non-HDL-p, LDL-p, and select subfractions of VLDL-p and LDL-p. During high-intensity statin therapy, on-treatment levels of LDL-c and atherogenic particles were associated with residual risk of CVD/all-cause death. Clinical Trial Registration Information —ClinicalTrials.gov. Identifier: NCT00239681.Background— Cardiovascular disease (CVD) can occur in individuals with low low-density lipoprotein (LDL) cholesterol (LDL-C). We investigated whether detailed measures of LDL subfractions and other lipoproteins can be used to assess CVD risk in a population with both low LDL-C and high C-reactive protein who were randomized to high-intensity statin or placebo. Methods and Results— In 11 186 Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) participants, we tested whether lipids, apolipoproteins, and ion mobility–measured particle concentrations at baseline and after random allocation to rosuvastatin 20 mg/d or placebo were associated with first CVD events (n=307) or CVD/all-cause death (n=522). In placebo-allocated participants, baseline LDL-C was not associated with CVD (adjusted hazard ratio [HR] per SD, 1.03; 95% confidence interval [CI], 0.88–1.21). In contrast, associations with CVD events were observed for baseline non–high-density lipoprotein (HDL) cholesterol (HR, 1.18; 95% CI, 1.01–1.38), apolipoprotein B (HR, 1.28; 95% CI, 1.11–1.48), and ion mobility–measured non-HDL particles (HR, 1.19; 95% CI, 1.05–1.35) and LDL particles (HR, 1.21; 95% CI, 1.07–1.37). Association with CVD events was also observed for several LDL and very-low-density lipoprotein subfractions but not for ion mobility–measured HDL subfractions. In statin-allocated participants, CVD events were associated with on-treatment LDL-C, non-HDL cholesterol, and apolipoprotein B; these were also associated with CVD/all-cause death, as were several LDL and very-low-density lipoprotein subfractions, albeit with a pattern of association that differed from the baseline risk. Conclusions— In JUPITER, baseline LDL-C was not associated with CVD events, in contrast with significant associations for non-HDL cholesterol and atherogenic particles: apolipoprotein B and ion mobility–measured non-HDL particles, LDL particles, and select subfractions of very-low-density lipoprotein particles and LDL particles. During high-intensity statin therapy, on-treatment levels of LDL-C and atherogenic particles were associated with residual risk of CVD/all-cause death. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00239681.