Depressed High-density Lipoprotein Research Articles

Clustered cardiovascular disease risk among children aged 8–13 years from lower socioeconomic schools in Gqeberha, South Africa

ObjectivesTo determine the prevalence of individual cardiovascular disease (CVD) risk factors and clustered CVD risk among children attending schools in periurban areas of Gqeberha and to investigate the independent association...

A Modern Approach to Dyslipidemia.

Lipid disorders involving derangements in serum cholesterol, triglycerides, or both are commonly encountered in clinical practice and often have implications for cardiovascular risk and overall health. Recent advances in knowledge, recommendations, and treatment options have necessitated an updated approach to these disorders. Older classification schemes have outlived their usefulness, yielding to an approach based on the primary lipid disturbance identified on a routine lipid panel as a practical starting point. Although monogenic dyslipidemias exist and are important to identify, most individuals with lipid disorders have polygenic predisposition, often in the context of secondary factors such as obesity and type 2 diabetes. With regard to cardiovascular disease, elevated low-density lipoprotein cholesterol is essentially causal, and clinical practice guidelines worldwide have recommended treatment thresholds and targets for this variable. Furthermore, recent studies have established elevated triglycerides as a cardiovascular risk factor, whereas depressed high-density lipoprotein cholesterol now appears less contributory than was previously believed. An updated approach to diagnosis and risk assessment may include measurement of secondary lipid variables such as apolipoprotein B and lipoprotein(a), together with selective use of genetic testing to diagnose rare monogenic dyslipidemias such as familial hypercholesterolemia or familial chylomicronemia syndrome. The ongoing development of new agents—especially antisense RNA and monoclonal antibodies—targeting dyslipidemias will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms.

Abstract P093: Correlates of Vascular Health in Children and Adolescents With Dyslipidemia

Introduction: Impaired vascular function and structure has been associated with cardiovascular risk factors such as elevated levels of Low Density Lipoprotein cholesterol (LDL-C) and triglycerides, depressed High Density Lipoprotein cholesterol (HDL-C), elevated blood pressure (BP) and body mass index (BMI) in children and young adults. These changes can result in premature coronary artery disease. The degree to which these measures predict vascular damage in children and adolescents is less clear. Hypothesis: We hypothesized that commonly used clinical and laboratory measures will predict vascular health as assessed by measures of carotid artery intima-media thickness (CIMT), pulse wave velocity (PWV), and augmentation index (Aix) in at risk youth. Methods: Children and adolescents with dyslipidemia (n=120, 13.1 ± 1.9 years old, 49% female (59 of 120)) were recruited from a pediatric preventive cardiology clinic. Non-fasting total cholesterol, HDL cholesterol, and triglycerides were obtained prior to the clinic visit. LDL-C and non-HDL-C were calculated with the Martin equation. Remnant particles were calculated as: total cholesterol minus (HDL-C + LDL-C). BP, height, weight, and waist circumference (WC) were measured at the clinic visit. WC was measured 2cm above the iliac crest by a single observer. Tobacco smoke exposure history was obtained using a parent questionnaire. PWV and Aix were measured using a SphygmoCor XCEL combined oscillometric and tonometric device. CIMT was measured via B mode ultrasound on the far wall of the left and right common carotid arteries using a semi-automated edge detection software. Multiple linear regression with backwards selection was used to identify the strongest predictors of CIMT, PWV, and normalized Aix. Results: Age (β=0.26; p=0.002), systolic BP (β=0.16; p=0.04), waist-to-height ratio (β=0.24; p=0.01), hemoglobin A1c (β=0.18; p=0.01) and presence of hypertriglyceridemic waist (defined as triglycerides ≥110mg/dL and WC ≥90 percentile) (β=0.28; p=0.006) were the strongest predictors of PWV (R2=0.353). Diastolic BP (β=0.21; p=0.01), waist-to-height percentile (β=0.22; p=0.01), and remnant particles (β=0.21; p=0.01) were the strongest predictors of normalized Aix (R2=0.175). Age (β=0.19; p=0.03), and systolic BP (β=0.28; p=0.002) were the strongest predictors of CIMT (R2=0.138). Triglycerides, history of tobacco smoke exposure, total cholesterol, LDL-C, HDL-C, and non-HDL-C were not predictive of CIMT, PWV, or normalized Aix. Conclusion: BP consistently predicted was the most common predictor of CIMT, PWV, and Aix in children and adolescents with dyslipidemia. Waist-to-height ratio/percentile was also a reliable predictor in both PWV and Aix. BP and abdominal obesity management should be a focus in this at risk population.

State of the science on cardiometabolic risk after spinal cord injury: recap of the 2013 Asia pre-conference on cardiometabolic disease.

Cardiovascular disease (CVD) is a leading cause of death in persons with spinal cord injury (SCI) who survive at least 1 year post injury. Persons with SCI who are younger than 45 years of age are four times more likely to die of cardiac causes than their age-matched counterparts without SCI. There is evidence that people with SCI are at increased risk for CVD compared to the general population, however prospective trials documenting true incidence have not confirmed this. These figures are not surprising, due to the effect of paralysis on body composition, challenges to physical activity, and the body’s response to physical activity after SCI. Individuals with SCI may also be less likely, depending on level of injury, to experience angina or other cardiac-related symptoms as a warning sign of cardiac compromise due to sympathetic nervous system disruption. Because measures of risk, and subsequent preventive practices, are based on and designed for the general population and because persons with SCI experience CVD earlier and with fewer cardiac symptoms than the general population, there is a need to better characterize the risks in this population.6 One of the significant risks of CVD in persons with SCI is their tendency to develop cardiometabolic syndrome, defined as a cluster of risk factors that includes obesity, insulin resistance, diabetes mellitus, dyslipidemia, and subclinical atherosclerosis. Cardiometabolic risk (CMR) has been a principal research focus of the Rehabilitation Research and Training Center (RRTC) on Secondary Conditions in the Rehabilitation of Individuals with Spinal Cord Injury. Research conducted during a previous cycle of SCI-RRTC (2003-2009) funding demonstrated that 76.9% of subjects exhibited risk clustering, with elevated low-density lipoprotein cholesterol (LDL-C) occurring in 64% of subjects and depressed high-density lipoprotein cholesterol (HDL-C) occurring in 53% of subjects (42% and 11%, respectively, for males and females). Further, overweight/obesity was the most prevalent CMR (74%) among 121 community-dwelling persons with chronic SCI. Body mass index (BMI) provides a proxy measure of body fat, as the ratio of weight (kg) and height (m2). Although BMI may be adequate for providing a gross estimate of obesity in the general population, it is problematic after SCI due to the significant changes in body composition that are nearly universal and are characterized by a loss of lean and increase in fat mass. As a result, the BMI scale significantly underestimates obesity in individuals after SCI and therefore may not signal actual risk. Similarly, although optimization of the lipid profile is integral to general population CVD prevention, the way in which lipid patterns may differ after SCI and how those differences impact CVD risk in persons with SCI have not received much attention.

Lipid abnormalities in foreign-born and US-born patients in a medical group

With an increasing foreign-born population in the United States, cardiovascular risk reduction through effective lipid treatment strategy is precluded by limited lipid profile information. This study compares the patterns of lipid abnormalities of foreign-born and US-born patients treated by a single medical group. We conducted a medical record review of 53,361 US-born and 6430 foreign-born patients in 2010. Compared with US-born, a higher proportion of foreign-born patients are younger than 40 years (26% vs 14%), receive Medicaid (24% vs 8%), and are less likely to be obese (26% vs 43%). More foreign-born patients have diabetes (25% vs 22%), are poor (4.7% vs 3.6%), and not on lipid-lowering drugs (63% vs 56%). Place of birth is not associated with total cholesterol levels. Adjusted for social and demographic characteristics, however, foreign-born are more likely than US-born to have elevated low-density lipoprotein cholesterol (adjusted difference, 2.1; 95% CI, 0.6-3.7), depressed high-density lipoprotein cholesterol (adjusted difference, 6.1; 95% CI, 4.4-7.8), and elevated triglycerides (adjusted difference, 2.4; 95% CI, 0.8-4.1). Foreign-born patients, on lipid-lowering medications, are more likely to still have elevated levels of low-density lipoprotein cholesterol (adjusted difference, 3.5; 95% CI, 1.4-5.6). Despite having a similar distribution of total cholesterol as their US-born counterparts, the other lipid fractions among foreign-born patients are more likely to be pathologic. Therefore, dyslipidemia screening tests need to include the lipid subfractions. The higher prevalence of dyslipidemias, both among foreign-born patients with and without lipid-lowering medications, challenges medical groups to intensify effective lipid treatment strategies.

Abstract 134: A Double Heterozygote for LCAT and ABCA1 Mutations Accounts for Severe Hypoalphalipoproteinemia

We report a family with extremely depressed high density lipoprotein (HDL) cholesterol (C) levels. The proband, a 27 year-old male of Asian Indian origin, was identified on routine lipid screening to have an HDL-C of 9mg/dL. His 24 year-old brother had an HDL-C of 6mg/dL and was therefore referred to a local lipid clinic in 1997. Both brothers were asymptomatic. The nuclear family was comprised of another brother and a mother living in India; their father had died previously from an undetermined cause. The parents were second cousins. Blood was obtained from members of the extended family and showed that the mother’s HDL-C was reduced at 29mg/dL, while the 3rd bother had a normal HDL-C at 54mg/dL. Based on the above scenario, a homozygous mutation most likely involving ABCA1 was presumed to be responsible for this lipoprotein profile. However, microsatellite marker analyses of the ABCA1 locus showed no homozygosity pattern in the two affected brothers. Further analyses of the APOA1-C3-A4 locus similarly failed to show homozygosity in the affected brothers. Plasma activities of both salt-stimulated paraoxanase and LCAT were at the low end of normal. Direct sequence analyses of the LCAT gene showed all three brothers were heterozygous for the Arg423His mutation, while the mother’s LCAT gene sequence was normal. No further work was pursued until 2011, when this family’s DNA was re-examined by direct sequencing. On this occasion, a heterozygous mutation in ABCA1 was found, namely Arg1270X in the 2 affected brothers and their mother. To our knowledge, this is the first report of ’double heterozygosity’ for LCAT and ABCA1 mutations producing severe hypoalphalipoproteinemia. Further, simple heterozygosity for the ABCA1 Arg1270X mutation had a co-dominant influence, moderately reducing HDL-C levels. In contrast, simple heterozygosity for the LCAT Arg423His mutation had no effect on HDL-C, but in the presence of ABCA1 Arg1270X it contributed to markedly reduced HDL-C. This case report highlights a potential pitfall in human genetic studies, namely assuming a particular inheritance pattern based upon family structure. It also highlights the value of perseverance by searching for causative mutations in more than one gene.

Abstract 495: High-Density Lipoprotein-Mediated Modulation of Autoimmunity in Normolipidemic Lupus-Prone Mice

The notion that quantitative and/or qualitative modulation of High-Density Lipoprotein (HDL) can protect against autoimmunity and the development of Systemic Lupus Erythematosus (SLE) is supported by demonstration of its anti-inflammatory and immunosuppressive properties in hypercholesterolemic rodent models lacking Apolipoprotein A-I (Apo A-I) or treated with 4F Apo A-I mimetic peptide. However, it is not known whether similar effects of Apo A-I (HDL) deficiency or 4F treatment are manifested in the absence of hypercholesterolemia, or whether raising HDL elicits opposite effects to those caused by Apo A-I deficiency. It also remains to be determined whether beneficial effects of 4F also include mitigation of SLE-associated HDL dysfunction (depressed HDL levels and PON-1 activity) that we previously showed was also inherent in normolipidemic SLE-prone gld mice. We transferred SLE from SLE-prone Sle123 mice into congenic wild-type, Apo A-I knockout or Apo A-I transgenic mice by bone marrow transplantation. Transgenic Apo A-I overexpression resulted in significant improvement in several Lupus phenotypes, including lower anti-DNA auto-antibodies, reduced in situ T lymphocyte proliferation, decreased activated CD4 + T lymphocytes and CD4 + effector/memory cells, and improved kidney pathology. Surprisingly, Apo A-I deficiency had no significant influence on the above Lupus phenotypes and, as with Apo A-I overexpression, did not affect CD4 + FoxP3 + regulatory T cell numbers. Feeding gld mice diet supplemented with 4F peptide (∼6mg/Kg body weight: synthesized from D-amino acids to make it orally bio-available) did not reduce auto-antibodies or modify any of the Lupus phenotypes above other than kidney pathology, which was significantly improved. Interestingly, this beneficial effect of 4F was mediated in the absence of any significant improvement in HDL levels or PON-1 activity. Considering that HDL deficiency did not modulate major Lupus phenotypes in the absence of hypercholesterolemia, we conclude that supra-physiologically high levels of Apo A-I (HDL) may be required to have broad therapeutic benefit, while Apo A-I mimetic peptide treatment may be a more clinically viable strategy to treat glomerulonephritis in SLE.

Iatrogenic Severe Depression of High‐Density Lipoprotein Cholesterol

The authors present 5 cases of paradoxical depression of high-density lipoprotein (HDL) cholesterol induced by fibrate drugs. In a 24-month review of all cases seen in one physician's practice at the Winnipeg Health Sciences Centre Lipid Clinic, 492 patients made a total of 1187 visits. Sixty-eight of them were given a fibrate drug (14%). Ten patients had HDL cholesterol levels that were less than 0.5 mmol/L (2%), and of these, 5 cases were due to exposure to fenofibrate (1%). These 5 cases comprised 7.4% of the 68 patients who were given any fibrate drug during that period. Mean levels were as follows: HDL cholesterol on fenofibrate 0.27, off fenofibrate 1.0 mmol/L and apo A1 on fenofibrate 0.41, off fenofibrate 1.17 g/L. A literature review revealed documented cases in 37 patients involving fibrates alone or in combination with other drugs known to cause decreased HDL cholesterol levels. In 13 patients, exposure was to fibrate therapy alone; in those exposed to combinations, the effect was clearly attributable to fibrates in 9; in 14, the nonfibrates (mostly rosiglitazone) were the attributable drugs; and in 1, it was impossible to tell. Thus, fibrate therapy should always be suspected as a cause of profoundly depressed HDL cholesterol.

Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3)

BackgroundFamilial partial lipodystrophy (Dunnigan) type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367) results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition.MethodsWe present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol.ResultsThe mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable.ConclusionTaken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

Treatment of dyslipidemia with lovastatin and ezetimibe in an adolescent with cholesterol ester storage disease

BackgroundCholesterol ester storage disease (CESD) is an autosomal recessive illness that results from mutations in the LIPA gene encoding lysosomal acid lipase. CESD patients present in childhood with hepatomegaly and dyslipidemia characterized by elevated total and low-density lipoprotein cholesterol (LDL-C), with elevated triglycerides and depressed high-density lipoprotein cholesterol (HDL-C). Usual treatment includes a low fat diet and a statin drug.ResultsIn an 18-year old with CESD, we documented compound heterozygosity for two LIPA mutations: a novel frameshift nonsense mutation and a deletion of exon 8. The patient had been treated with escalating doses of lovastatin for ~80 months, with ~15% decline in mean LDL-C. The addition of ezetimibe 10 mg to lovastatin 40 mg resulted in an additional ~16% decline in mean LDL-C.ConclusionThese preliminary anecdotal findings in a CESD patient with novel LIPA mutations support the longer term safety of statins in an adolescent patient and provide new data about the potential efficacy and tolerability of ezetimibe in this patient group.

R219K polymorphism of the ABCA1 gene and its modulation of the variations in serum high-density lipoprotein cholesterol and triglycerides related to age and adiposity in white versus black young adults. The bogalusa heart study

Mutations in adenosine triphosphate (ATP)-binding cassette transporter 1 (ABCA1) gene have been established as the molecular defect in Tangier disease and familial hypoalphalipoproteinemia, uncommon genetic disorders characterized by deficient or depressed high-density lipoprotein (HDL) cholesterol and increased triglycerides. However, information regarding the frequency of common variants, including Arg219Lys (R219K) within the coding region of the ABCA1 gene and their effect on these phenotypes in the general population is limited. This study examined the frequency and phenotypic effect of R219K variant in a community-based sample of 887 white and 390 black young adults aged 20 to 38 years. The frequency of the variant allele (K219) was higher in blacks than in whites (0.595 v 0.262, P < .001), with carriers (KK+RK) representing 83.8% of blacks versus 44.2% of whites. After adjusting for age, body mass index (BMI), and sex, the genotype effect on HDL cholesterol and natural logarithm of triglycerides was not apparent in whites or blacks. However, significant interaction effects of genotype and age on HDL cholesterol ( P < .001) and genotype and BMI on triglycerides ( P = .029) were found in whites. Carriers (KK+RK), unlike noncarriers (RR) showed a positive relationship between age and HDL cholesterol (regression coefficient β = 0.28, P = .029 for carriers v β = −0.18, P = .112 for noncarriers). In addition, the variant allele attenuated the adverse positive relationship between BMI and triglycerides (β = 0.032, P < .001 for carriers v β = 0.046, P < .001 for noncarriers). These results indicate that the K219 allele frequency differs markedly between blacks and whites, and that the variant-allele modulates the association between age and HDL cholesterol, as well as body fatness and triglycerides in a beneficial manner only in whites.

Low-Density Lipoprotein Subclass Distribution Pattern and Adiposity-Associated Dyslipidemia in Postmenopausal Women

Objective: A predominance of small, dense low-density lipoprotein (LDL) particles (subclass pattern B) is associated with increased risk for coronary heart disease and is characterized by elevated triglycerides and depressed high-density lipoprotein (HDL) cholesterol concentrations. The present analysis was undertaken to assess the impact of LDL subclass distribution pattern and adiposity on serum lipids in postmenopausal women.Methods: Anthropometric measurements and fasting lipid data were obtained from 254 postmenopausal women 70 years of age or younger, not receiving sex hormone replacement, who were participating in a clinical trial designed to assess the influence of hormone replacement regimens on coronary heart disease risk markers.Results: The prevalence of LDL subclass pattern B was 32%. Triglyceride levels were higher and HDL cholesterol lower (both p<0.001) in women with pattern B vs. pattern A, but total and LDL cholesterol levels did not differ. LDL subclass pattern contributed independently to the variance in HDL cholesterol (p<0.001) and loge triglyceride (p<0.001) concentrations explained by anthropometric variables (waist circumference or body mass index). Compared to women with LDL subclass pattern A and waist circumference below the median value of 83.0 centimeters, those with pattern B and waist ≥83.0 centimeters had markedly lower HDL cholesterol levels [44.0 (41.6–47.4) vs. 57.2 (54.1–60.3) mg/dL, mean (95% CI)] and increased triglyceride concentrations [geometric mean 147.8 (131.6–165.7) vs. 95.4 (88.2–102.5) mg/dL].Conclusions: These data suggest that adiposity and LDL subclass distribution pattern are independent determinants of plasma triglyceride and HDL cholesterol concentrations in postmenopausal women.

Serum lipid profiles in Malay mothers and neonates: a cross-sectional study.

Preliminary epidemiological data suggest that dyslipidaemia contributes significantly to rising mortality due to atherosclerosis in Peninsular Malays. The aim of this study was to determine whether abnormal serum lipid profiles are present at birth in this population. The patients were 487 non-diabetic Malay women who had an uncomplicated antenatal course and delivered healthy singleton babies at term. Cord blood and maternal post-partum venous blood samples were taken for assay of serum cholesterol and triglyceride concentrations using standard enzymatic methods. Maternal total serum cholesterol concentrations (mean +/- SD; 7.5 +/- 2.5 mmol/L) were higher than in other reported series (range of published means 5.2-6.5 mmol/L) with a correspondingly low high-density lipoprotein (HDL): total cholesterol ratio. The mean cord blood total serum cholesterol (1.7 +/- 1.0 mmol/L) was consistent with previously reported population means (1.5-1.9 mmol/L) but there was a relatively high low-density lipoprotein (LDL)-cholesterol and depressed HDL: cholesterol ratio. Significant correlations between maternal and neonatal serum total (P = 0.038) and especially HDL-cholesterol (P < 0.001) were observed. Maternal and cord blood serum triglyceride levels were comparable to those in other series. These cross-sectional data provide evidence that abnormal serum cholesterol profiles are found in pregnant Malay women and their neonates which may have implications for the prevalence of macrovascular disease in the Malay population.

Uptake of high-density lipoprotein by Y-organs of the crab Cancer antennarius: III. Evidence for adsorptive endocytosis and the absence of lysosomal processing.

Ecdysteroid hormones in crustaceans are synthesized from cholesterol in the Y-organs. Circulating cholesterol is bound to high-density lipoprotein (HDL). Experiments were conducted to find the mode of cholesterol uptake by Y-organ cells. The working hypothesis is as follows: Cholesterol is taken up by endocytosis of the entire HDL-cholesterol complex. HDL was doubly labeled in the apolipoprotein and cholesterol components with 125I and 3H, respectively. The time courses of uptake of the two labels by Y-organ segments in vitro were parallel throughout 24 hr of incubation. Chloroquine, an inhibitor of lysosomal function, had no effect on the uptake and degradation of HDL. Cycloheximide, an inhibitor of protein synthesis, depressed HDL uptake. Transmission electron microscopy of Y-organ tissue showed features characteristic of adsorptive endocytosis, including coated pits in the plasma membranes and their invagination and vesiculation. Visualization of HDL with immunogold binding showed profiles consistent with endocytosis. Quantitation of the distribution of HDL-gold particles indicated that about 75% were associated with cellular formed elements, but not with lysosomes, and significantly more particles overall were present in cells from de-eyestalked crabs than those from intact crabs. These data demonstrate that (a) cholesterol-carrying HDL is taken into Y-organ cells by adsorptive endocytosis, (b) its uptake is dependent on de novo protein synthesis, (c) its intracellular processing is independent of lysosomal enzymes, and (d) its uptake is depressed by the molt-inhibiting hormone secreted by the eyestalks.

Prevalence of hypercholesterolaemia and coronary heart disease risk factors among Southeast Asian refugees in a primary care clinic

The National Cholesterol Education Program's guidelines for the detection, evaluation, and treatment of high serum cholesterol in adults were employed in screening 155 Southeast Asian refugees in a primary care clinic in Seattle, Washington. In order to determine the need for a therapeutic intervention, information also was collected on the presence of other coronary heart disease (CHD) risk factors. Male gender (39%), cigarette smoking (27%) and hypertension (26%) were the most common CHD risk factors; diabetes mellitus, obesity, a family or prior history of CHD or cerebral/peripheral vascular disease were each noted in less than 10%. The mean serum total cholesterol was 194 mg/dl. Thirty-seven (24%) patients required further lipoprotein analysis based on cholesterol level, history of CHD and risk factors for CHD. Twenty-one (66%) of 32 patients who underwent lipoprotein analysis (14% of all patients) were candidates for a therapeutic intervention for hypercholesterolaemia. Additionally, 14 (44%) patients undergoing lipoprotein analysis had depressed high-density lipoprotein levels (< 35 mg/dl). We conclude that CHD risk factors including hypercholesterolaemia are common in Southeast Asian refugee clinic patients and that in many, a therapeutic intervention may well be justified. Southeast Asian refugees should be routinely screened for hypercholesterolaemia and other CHD risk factors in accordance with the National Cholesterol Education Program's guidelines.

Insights into the pathogenesis and prevention of coronary artery disease.

To present information about risk factor clustering and the oxidation hypothesis of atherosclerosis and attempt to synthesize these facts into a clinically relevant approach to patients with or at risk for coronary artery disease (CAD). The total cholesterol level is a relatively weak marker for the risk of CAD. The levels of both high-density lipoprotein (HDL) cholesterol and remnants of triglyceride-rich lipoproteins and the inherent susceptibility of the low-density lipoprotein (LDL) particles to oxidative modification may be as important as the total or LDL cholesterol levels. LDL cholesterol must undergo oxidative modification by means of oxygen free radical processes before it becomes atherogenic. Patients with high levels of oxidative stress include those with risk factor clustering or insulin resistance (or both). Such patients are characterized by hypertension, truncal obesity, hypertriglyceridemia, depressed HDL cholesterol levels, and increased insulin levels. They also have increased levels of triglyceride-rich remnant lipoproteins and LDL particles that are characterized by their small dense nature and pronounced predisposition to oxidative modification. Biologic antioxidants seem to be promising therapy for the prevention of atherogenesis. Although long-term prospective data are not yet available, vitamin E has been shown to be effective in both animal and human models in preventing LDL oxidation, and it may have a role in the prevention of CAD. A healthy diet of fresh fruits, vegetables, and whole grains is beneficial because it improves the lipid levels and provides high levels of natural antioxidants. The atherogenic potential of hydrogenated polyunsaturated fats is approximately equivalent to that of saturated fats. Monounsaturated fat is inherently resistant to oxidation and may be protective against CAD. Niacin may be effective in patients with clustered risk factors. It has been found to convert the easily oxidized small dense LDL pattern to the large buoyant oxidation-resistant particles. Hydroxymethylglutaryl-coenzyme A reductase inhibitors are well tolerated and highly effective in decreasing LDL cholesterol, but they are expensive. Estrogen has multiple potentially beneficial effects relative to cardiovascular disease. Persons with or at high risk for CAD should be identified early and aggressively treated with a program that involves lifestyle changes, alterations in dietary intake, and pharmacologic therapy.

Changes in lipids and lipoproteins with long-term estrogen deficiency and hormone replacement therapy

Cross-sectional data of the long-term effects of estrogens, androgens, and progestogens on lipids and lipoproteins were obtained in 556 postmenopausal women aged 24 to 85 years with follow-up for 1 to 44 years. Baseline values were obtained in 155 women from less than 1 year up to 30 years after menopause. Total cholesterol and low-density lipoprotein cholesterol tended to rise during the early postmenopausal years while high-density lipoprotein cholesterol did not change. Triglycerides were related to weight and were significantly different only between untreated women of normal weight (128.3 +/- 7.80 mg/dl) and hormone users weighing greater than 200 pounds (252.9 +/- 9.44 mg/dl), p less than or equal to 0.001. Although mean high-density lipoprotein cholesterol was lower with both C-21 progestogens (64.5 +/- 4.16 mg/dl) and C-19 progestogens (61.9 +/- 3.84 mg/dl), there were no statistically significant differences on comparison with levels in the unopposed estrogen users (67.0 +/- 3.94 mg/dl). Smoking significantly depressed high-density lipoprotein cholesterol in both hormone users (p less than or equal to 0.001) and untreated women (p less than or equal to 0.001). Added progestogens do not adversely affect lipids and lipoproteins over the long term when adequate dosages of estrogens are used.

Lipoprotein Analysis in Bodybuilders

The use of anabolic steroids to augment athletic performance is widespread. It is known that these drugs can adversely affect lipoproteins in normal volunteers, leading to increased cholesterol and low density lipoprotein and depressed high density lipoprotein. It has been shown that endurance type exercise can lead to beneficial effects on lipoproteins but the effects of power exercise are less clear-cut and made more difficult to interpret by prior anabolic steroid use. This paper details the lipoprotein results in 24 subjects, eight sedentary controls, eight non-steroid and eight steroid using bodybuilders. The results revealed no significant difference between sedentary controls and non-steroid bodybuilders suggesting that this form of training does not cause beneficial effects on lipoproteins. However, the steroid-using groups had higher cholesterol and low density lipoprotein, with lower high density lipoprotein, high density lipoprotein2, high density lipoprotein3 and high density lipoprotein2/high density lipoprotein3 ratios compared to the other two groups. The long-term effects of such results may be an increased risk of atherosclerosis and requires long-term follow-up.

Genetic factors influencing apolipoprotein AI and AII levels in a kindred with premature coronary heart disease.

A single 51-member kindred, ascertained on the basis of a normotriglyceridemic proband with depressed high-density lipoprotein cholesterol (HDL-C) and myocardial infarctions at ages 40 and 42, was studied with respect to quantitative variation in HDL-C and apolipoprotein (apo) AI and AII levels. The results of bivariate segregation analysis suggest that the etiology of depressed HDL-C involves one or possibly two major loci: one has a pleiotropic effect on apo AI and apo AII levels and, possibly another one that affects apo AI levels. Both the major loci were characterized as having a dominant allele leading to depression of the respective trait(s). In addition, analysis of the cosegregation of HDL-C and apo AI levels gave evidence of residual nonfamilial factors common to both traits, leading to a positive covariance between them. This could reflect the role of apo AI in the transformation of nascent HDL-C particles into mature ones via its cofactor activity to lecithin cholesterol acyltransferase. The proposed two-locus model represents one possible etiology for the heterogeneous disorder of hypoalphalipoproteinemia. This analysis of a single pedigree does not completely define the genetic mechanism, but it does illustrate a useful new analytic approach.

Normalization of triglycerides in type IV hyperlipoproteinemia fails to correct low levels of high-density-lipoprotein cholesterol.

High-density-lipoprotein (HDL) cholesterol protects against coronary heart disease, and ways to raise low HDL values are being sought. Cross-sectional population surveys have shown that HDL cholesterol is inversely related to plasma triglycerides, yet to our knowledge no longitudinal studies have shown that a decrease in elevated triglycerides will raise depressed HDL levels. We therefore used dietary therapy to lower the triglyceride levels of 29 men with Type IV hyperlipoproteinemia and evaluated the effects on HDL-cholesterol levels. Despite a reduction in triglyceride levels from 697 +/- 90 to 333 +/- 37 mg per deciliter (P < 0.01), initially low HDL-cholesterol values did not change (29 +/- 1 to 30 +/- 1 mg per deciliter). Even in a subgroup of 12 men whose triglyceride levels fell to normal (from 670 +/- 99 to 170 +/- 7, P < 0.01) and whose weight and triglycerides remained stable for two years, HDL cholesterol remained unchanged (29 +/- 1 vs. 32 +/- 1). The persistently low HDL-cholesterol level in the presence of normalization of triglycerides suggests that depressed HDL cholesterol may be an independent metabolic abnormality in Type IV hyperlipoproteinemia.