Low Serum High-density Lipoprotein Research Articles

Autosomal recessive hypercholesterolemia in three sisters with phenotypic homozygous familial hypercholesterolemia: diagnostic and therapeutic procedures.

Familial hypercholesterolemia is an autosomal-dominant inherited disorder caused by mutations in the low-density lipoprotein (LDL) receptor gene. The homozygous form is characterized by high-serum LDL cholesterol concentrations, xanthoma formation and premature atherosclerosis. Recently, another molecular defect that also results in severely elevated LDL cholesterol levels was identified: autosomal recessive hypercholesterolemia. This inherited disorder is caused by a mutation in a putative LDL receptor adaptor protein. In our lipid clinic, three sisters with phenotypic homozygous hypercholesterolemia were recently diagnosed as having autosomal recessive hypercholesterolemia. They presented in 1990 with massive tuberous xanthomas at the knees, thighs, elbows and buttocks. LDL receptor and apolipoprotein B gene defects were excluded through mutation analysis. From 1992 onward they underwent LDL-apheresis on a weekly basis. To date the clinical outcome is very satisfying with no evidence of coronary heart disease or aortic valve lesions and almost complete regression of xanthomatosis.

Metabolic effects of fluvastatin extended release 80 mg and atorvastatin 20 mg in patients with type 2 diabetes mellitus and low serum high-density lipoprotein cholesterol levels: a 4-month, prospective, open-label, randomized, blinded—end point (probe) trial

BackgroundDiabetic dyslipidemia is characterized by greater triglyceridation of all lipoproteins and low levels of plasma high-density lipoprotein cholesterol (HDL-C). In this condition, the serum level of low-density lipoprotein cholesterol (LDL-C) is only slightly elevated. The central role of decreased serum HDL-C level in diabetic cardiovascular disease has prompted the establishment of a target of ≥50 mg/dL in patients with diabetes mellitus (DM). ObjectiveThe aim of the study was to assess the effects of once-daily administration of fluvastatin extended release (XL) 80 mg or atorvastatin 20 mg on serum HDL-C levels in patients with type 2 DM and low levels of serum HDL-C. MethodsThis 4-month, prospective, open-label, randomized, blinded—end point (PROBE) trial was conducted at Endocrinology and Diabetology Service, L. Sacco-Polo University Hospital (Milan, Italy). Patients aged 45 to 71 years with type 2 DM receiving standard oral antidiabetic therapy, with serum HDL-C levels ≤50 mg/dL, and with moderately high serum levels of LDL-C and triglycerides (TG) were enrolled. After 1 month of lifestyle modification and dietary intervention, patients who were still showing a decreased HDL-C level were randomized, using a 1:1 ratio, to receive fluvastatin XL 80-mg tablets or atorvastatin 20-mg tablets, for 3 months. Lipoprotein metabolism was assessed by measuring serum levels of LDL-C, HDL-C, TG, apolipoprotein (apo) A-I (the lipoprotein that carries HDL), and apo B (the lipoprotein that binds very low-density lipoprotein cholesterol, intermediate-density lipoprotein, and LDL on a molar basis). Patients were assessed every 2 weeks for treatment compliance and subjective adverse events. Serum creatine phosphokinase and liver enzymes were assessed before the run-in period, at the start of the trial, and at 1 and 3 months during the study. ResultsOne hundred patients were enrolled (50 patients per treatment group; fluvastatin XL group: 33 men, 17 women; mean [SD] age, 58 [12] years; atorvastatin group: 39 men, 11 women; mean [SD] age, 59 [11] years). In the fluvastatin group after 3 months of treatment, mean (SD) LDL-C decreased from 149 (33) to 95 (25) mg/dL (36%; P ≤ 0.01), TG decreased from 437 (287) to 261 (164) mg/dL (40%; P ≤ 0.01), and HDL-C increased from 41 (7) to 46 (10) mg/dL (12%; P ≤ 0.05). In addition, apo A-I increased from 118 (18) to 124 (15) mg/dL (5%; P ≤ 0.05) and apo B decreased from 139 (27) to 97 (19) mg/dL (30%; P ≤ 0.05). In the atorvastatin group, LDL-C decreased from 141 (25) to 84 (23) mg/dL (40%; P ≤ 0.01) and TG decreased from 411 (271) to 221 (87) mg/dL (46%; P ≤ 0.01). Neither HDL-C (41 [7] vs 40 [6] mg/dL; 2%) nor apo A-I (117 [19] vs 114 [19] mg/dL; 3%) changed significantly. However, apo B decreased significantly, from 131 (20) to 92 (17) mg/dL (30%; P ≤ 0.05). Mean changes in HDL-C (+5 [8] vs −1 [2] mg/dL; P ≤ 0.01) and apo A-I (+6 [18] mg/dL vs −3 [21] mg/dL; P ≤ 0.01) were significantly greater in the fluvastatin group than in the atorvastatin group, respectively. However, the decreases in LDL-C (54 [31] vs 57 [32] mg/ dL), TG (177 [219] vs 190 [65] mg/dL), and apo B (42 [26] vs 39 [14] mg/dL) were not significantly different between the fluvastatin and atorvastatin groups, respectively. No severe adverse events were reported. ConclusionsFluvastatin XL 80 mg and atorvastatin 20 mg achieved mean serum LDL-C (≤ 100 mg/dL) and apo B target levels (≤ 100 mg/dL) in the majority of this population of patients with type 2 DM, but mean serum HDL-C level was increased significantly only with fluvastatin—16 patients (32%) in the fluvastatin group compared with none in the atorvastatin group achieved HDL-C levels ≥50 mg/dL. The increase in HDL-C in the fluvastatin-treated patients was associated with an increase in apo A-I, suggesting a potential pleiotropic and selective effect in patients with low HDL-C levels.

PPARα controlling HDL metabolism and atherosclerosis

Low serum high-density lipoprotein (HDL) cholesterol concentrations are a feature of the metabolic syndrome that is increasingly being recognized as an important risk factor for cardiovascular disease. HDL is a key mediator of reverse cholesterol transport (RCT), a pathway transporting cholesterol from extrahepatic cells and tissues to the liver for excretion. HDL metabolism is controlled by the interaction of its protein constituents, the apolipoproteins, such as apoA-I and apoA-II, with different enzymes (LCAT, HL, LPL), transfer proteins (CETP, PLTP,…) and lipoprotein receptors (ABCA-1, SR-BI,…). The level of expression of most of these proteins is partly controlled at the level of transcription by transcription factors, among which are the nuclear receptors. Nuclear receptors are activated by small lipophilic signalling molecules. Among these nuclear receptors, peroxisome proliferator-activated receptors were first identified to play a role in the control of lipid metabolism. In this paper, we will focus on the role of PPARα in HDL metabolism, its molecular action mechanism and its potential as pharmacological targets for future drug discovery.

Albuminuria and cardiovascular risk in hypertensive patients with left ventricular hypertrophy: the life study

Background:Peripheral endothelial dysfunction has been demonstrated in hypertension. However, its relationship to blood pressure (BP) load, vascular structure, and metabolic disturbances in patients with long-standing, previously treated hypertension is unclear.Methods:A total of 41 patients with stage I to III essential hypertension and electrocardiographic left ventricular hypertrophy were studied. After 2 to 3 weeks of placebo treatment we measured nitroprusside-induced relaxation (NIR), acetylcholine-induced relaxation (AIR), and media:lumen ratio in isolated, subcutaneous resistance arteries by myography, as well as 24-h ambulatory BP, and serum lipids.Results:Maximal AIR correlated negatively with median 24-h diastolic BP (r = −0.42, P = .01), and sensitivity to AIR correlated negatively with serum low density lipoprotein (LDL) (r = −0.36, P < .05). In multiple regression analyses, sensitivity to AIR correlated negatively with serum LDL (β = −0.33) independently of maximal NIR (β = 0.41) (adjusted R2 = 0.26, P < .01). Maximal acetylcholine-induced relaxation correlated negatively with median 24-h diastolic BP (β = −0.38) independently of maximal NIR (β = 0.45) (adjusted R2 = 0.32, P < .001). Acetylcholine-induced relaxation was not significantly related to diabetes or to media:lumen ratio (r = −0.26, NS).Conclusions:High diastolic BP and high serum LDL were associated with impaired maximal AIR and reduced sensitivity to AIR, respectively, independently of smooth muscle cell responsiveness to nitroprusside. This indicated decreasing endothelial function in small resistance arteries with increasing BP and increasing LDL in hypertension. Endothelial function was not significantly related to vascular structure of the resistance arteries or to diabetes in these patients with long-standing hypertension.

833-4 Undertreatment of low serum high-density lipoprotein cholesterol in patients with acute myocardial infarction

833-4 Undertreatment of low serum high-density lipoprotein cholesterol in patients with acute myocardial infarction

Criteria for medical intervention in obese children: a new definition of 'obesity disease' in Japanese children.

The Committee of the Japan Society for the Study of Obesity reported the new criteria for 'obesity disease' for Japanese adults in 2000. We defined the criteria for the diagnosis of obesity in children with medical problems, corresponding to the 'obesity disease' criteria in adults. Obesity in childhood was defined as follows: percentage of overweight (POW) and body fat exceeded the criteria. 'Obesity disease in childhood' was defined as obesity associated with health or medical problems, and with indications for medical intervention. Medical problems with indications for immediate intervention were grouped as A problems, which consisted of (i). hypertension; (ii). sleep apnea or hypoventilation; (iii). Type 2 diabetes mellitus or impaired glucose tolerance; and (iv). increased waist circumference or accumulation of visceral adipose tissue. Metabolic derangements or equivalent associated with obesity were grouped as B problems: (i). liver dysfunction; (ii). hyperinsulinemia; (iii). hypercholesterolemia; (iv). hypertriglyceridemia; (v). low serum high-density lipoprotein cholesterol; (vi). acanthosis nigricans, and (vii). hyperuricemia. Obese children over 5 years of age with following conditions were diagnosed as 'obesity disease in childhood': (i). any 'A problem', (ii) POW >or= 50% and any 'B problem', or (3) POW < 50% and more than one 'B problem' or equivalent. We decided to take physicosocial problems related to obesity into consideration as the criteria. The resultant criteria are proposed by the Committee for Research of Appropriate Body Build in Children*.

Leptin receptor polymorphism is associated with serum lipid levels and impairment of cholesterol lowering effect by simvastatin in Japanese men

Objective: To investigate whether leptin receptor (Ob-R) Arg223Gln polymorphism influences serum lipid levels and whether this polymorphism affects the efficiency of the cholesterol lowering HMG-CoA reductase inhibitor, simvastatin [Clin. Cardiol. 16 (1993) 317]. Design: Case–control association study. Subjects: We studied 201 Japanese men without medical care, and 78 Japanese who took simvastatin. Methods: Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Serum lipid and leptin levels were determined. Results: Subjects with the Arg/Arg homozygotes had significantly higher serum total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (TC: Arg/Arg: 213±3, Arg/Gln: 196±6, Gln/Gln: 184±5, P=0.004 for comparison among three genotypes, P=0.008 for difference between Arg/Arg and Arg/Gln, and P=0.025 for difference between Arg/Arg and Gln/Gln, LDL-C: Arg/Arg: 127±3, Arg/Gln: 112±6, Gln/Gln: 114±8, P=0.027) for comparison among three genotypes and P=0.011 for difference between Arg/Arg and Arg/Gln. Subjects with the Arg/Arg homozygotes had significantly lower serum high density lipoprotein cholesterol (HDL-C) levels than those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (Arg/Arg: 55±1, Arg/Gln: 62±3, Gln/Gln: 57±7, P=0.046) for comparison among three genotypes and P=0.013 for difference between Arg/Arg and Arg/Gln. In addition, in 78 patients with hypercholesterolemia who took 5 mg simvastatin, the TC lowering effect by simvastatin in subjects with the Arg/Arg homozygotes was significantly lower than in those with the Arg/Gln heterozygotes and Gln/Gln homozygotes (the reduction in serum TC levels; 62±4 vs. 79±6, P=0.044). Conclusions: We demonstrate that Ob-R Arg223Gln polymorphism in Japanese men is associated with significant elevation of serum TC and LDL-C levels. Our data also show that the Arg/Arg homozygotes tend to show lowered level of serum HDL-C. Furthermore, this polymorphism tends to show an attenuated response to an HMG-CoA reductase inhibitor in terms of the cholesterol lowering effect. These results suggest that the Ob-R gene may serve as a novel modifier gene for hypercholesterolemia in Japanese men.

Mild cognitive deterioration with subcortical features: prevalence, clinical characteristics, and association with cardiovascular risk factors in community-dwelling older persons (The InCHIANTI Study).

To identify subjects with minimal or mild nonamnestic cognitive impairment with parkinsonian stance and gait and investigate vascular correlates of this condition. First wave of an epidemiological longitudinal study (InCHIANTI) on factors predicting loss of mobility in older persons. The Chianti geographic area (Tuscany, Italy). Five hundred fifty-six subjects aged 70 to 90 with Mini-Mental State Examination (MMSE) scores greater than 23 of 30, of the 1,260 persons aged 65 and older randomly selected from the population registry of Greve in Chianti and Bagno a Ripoli, two small towns near Florence. Low cognitive performance (LCP) was defined as an age- and education-adjusted MMSE below the 50th percentile for the InCHIANTI population. Subcortical features were plastic rigidity on neurological examination (parkinsonism), gait disturbance (small-step gait or parkinsonian gait), and dysexecutive features. Two hundred forty-three participants had high cognitive performance, 166 had LCP without subcortical features, and 75 had LCP with subcortical features. Vascular risk factors were hypertension, atrial fibrillation or pathological findings on electrocardiogram (ECG), low serum high-density lipoprotein (HDL) or high low-density lipoprotein cholesterol, diabetes mellitus, obesity, and heavy smoking. Three main vascular risk factors were significantly more prevalent in LCP with subcortical features: hypertension (P =.02), atrial fibrillation or ECG changes (P =.04), and low HDL cholesterol (P =.001). LCP with subcortical features was significantly associated with cerebrovascular risk factors (P =.001). Gait disturbance and nonamnestic cognitive symptoms might be the consequence of subcortical vascular damage.

Effect of statins on mortality and cardiovascular events in elderly high-risk persons.

Review of: MRC/BHF Heart Protection Study of Cholesterol Lowering with Simvastatin in 20,536 High-Risk Individuals: a Randomized Placebo-Controlled Trial. Lancet 2002;360:7–22. PURPOSE: To determine the effect of simvastatin 40 mg daily versus placebo on all-cause mortality and cardiovascular events in high-risk persons with serum total cholesterol levels of 135 mg/dL or greater. BACKGROUND: Pooled data from three secondary prevention trials of patients with coronary artery disease (CAD) and two primary prevention studies showed that treatment of hypercholesterolemia with statins caused a 31% reduction in major coronary events (95% confidence interval (CI) = 26–36%) and a 21% reduction in all-cause mortality (95% CI = 14–28%).1 The secondary prevention trials included 4,444 persons (23% aged 65–70) treated with simvastatin in the Scandinavian Simvastatin Survival Study,2,3 4,159 persons (31% aged 65–75) treated with pravastatin in the Cholesterol and Recurrent Events Trial,4–6 and 9,014 persons (39% aged 65–75) treated with pravastatin in the long-term Intervention with Pravastatin in Ischaemic Disease Trial.7 The two primary prevention studies included 6,595 middle-aged men up to 64 years of age treated with pravastatin in the West of Scotland Coronary Prevention Study8 and 6,605 persons (22% aged 65–73) treated with lovastatin in the Air Force/Texas Coronary Atherosclerosis Prevention Study.9 The absolute risk reduction in major coronary events per 1,000 persons treated in these five studies was 33 (13–52) for women versus 37 (29–44) for men and 44 (30–58) for persons aged 65 and older versus 32 (24–40) for younger persons.1 METHODS: The Heart Protection Study included 20,536 persons (15,454 men and 5,082 women) aged 40 to 80 (5,806 aged 70–80) with serum total cholesterol of 135 mg/dL or greater and prior myocardial infarction (MI) (8,510 persons), other CAD (4,876 persons), or no CAD (7,150 persons). Of the 7,150 participants without CAD, 1,820 had cerebrovascular disease, 2,701 had peripheral arterial disease (PAD), and 3,982 had diabetes mellitus. Although treated hypertension was present in 8,457 persons, only 237 persons were included on the basis of hypertension alone. Patients were randomized to simvastatin 40 mg daily or double-blind placebo. Mean follow-up was 5 years. Average compliance was 85% for the simvastatin-treated group, and 17% of the placebo group took a statin during the 5-year study. RESULTS: During the 5-year study, simvastatin reduced serum total cholesterol 46 mg/dL, serum low-density lipoprotein (LDL) cholesterol 39 mg/dL, and serum triglycerides 12 mg/dL and increased serum high-density lipoprotein (HDL) cholesterol 1 mg/dL Simvastatin caused a 13% reduction in all-cause mortality (95% CI = 6–19%), a 17% reduction in any vascular death (95% CI = 9–25%), a 27% reduction in major coronary events (95% CI = 21–33%), a 25% reduction in any stroke (95% CI = 15–34%), a 24% reduction in coronary or noncoronary revascularization (95% CI = 17–30%), and a 24% reduction in any major vascular event (95% CI = 19–28%). Simvastatin significantly reduced the first major vascular event in patients with MI, other CAD, or no CAD; in patients with cerebrovascular disease, PAD, diabetes mellitus, treated hypertension, or no hypertension; in men and in women; in patients aged 40 to 64, 65 to 69, and 70 to 80; in patients with low or high serum total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides; in smokers and nonsmokers; and in patients treated with and without aspirin, beta blockers, and angiotensin-converting enzyme inhibitors. In the 3,500 persons with an initial serum LDL cholesterol of less than 100 mg/dL, reduction of serum LDL cholesterol from 97 mg/dL to 65 mg/dL by simvastatin caused a similar reduction in risk, as did treating patients with higher serum LDL cholesterol levels. Five years of simvastatin therapy prevented MI, stroke, and revascularization in 70 to 100 per 1,000 treated patients. CONCLUSION: In patients with serum total cholesterol of 135 mg/dL or higher at high risk for vascular events, simvastatin 40 mg daily significantly reduced all-cause mortality, vascular death, major coronary events, coronary or noncoronary revascularization, and any major vascular event regardless of initial levels of serum lipids, age, or gender.

Forearm hyperemia is a better marker than carotid intima-media thickness or ankle-brachial index for coronary artery disease in Japanese males under 65.

Forearm hyperemia, carotid intima-media thickness (IMT), and ankle-brachial pressure index (ABI) are subclinical markers associated with coronary artery disease (CAD). However, it is not known which marker is most highly correlated with CAD. We therefore compared these three parameters in the same patients under 65 years of age. In 40 males with documented CAD (mean age, 53 years), we measured forearm hyperemia by plethysmography, carotid IMT by B-mode ultrasound, and ABI by Doppler ultrasonography. Microalbuminuria, serum lipids, glucose and C-reactive protein (CRP) were also measured. Thirteen normal males served as controls (mean age, 49 years). Compared with normal subjects, CAD patients had lower hyperemia (42 vs. 92%; p < 0.001) and greater carotid IMT (0.81 vs. 0.67 mm; p < 0.01), but ABI was similar. The sensitivity of forearm hyperemia (72%) was higher than that of carotid IMT (22%) or ABI (3%) (abnormal criteria: forearm hyperemia < 60%, carotid IMT 21.0 mm, and ABI < 0.9). The patients had higher serum low-density lipoprotein (LDL) cholesterol, glucose and CRP, and lower high-density lipoprotein (HDL) cholesterol than the controls. Albuminuria was present in 49% of patients. Subclinical markers were further analyzed by age (35-54 vs. 55-64 years). The sensitivity of carotid IMT was lower in the younger patients (4% vs. 33%), while that of forearm hyperemia (69% vs. 75%) and albuminuria (47% vs. 52%) did not change with age. While carotid ultrasound was useful in older patients ( > or = 55 years), forearm hyperemia and microalbuminuria were sensitive markers irrespective of age. ABI was not useful in the Japanese men with CAD under age 65.

Association testing by DNA pooling: an effective initial screen.

With an ever-increasing resource of validated single-nucleotide polymorphisms (SNPs), the limiting factors in genome-wide association analysis have become genotyping capacity and the availability of DNA. We provide a proof of concept of the use of pooled DNA as a means of efficiently screening SNPs and prioritizing them for further study. This approach reduces the final number of SNPs that undergo full, sample-by-sample genotyping as well as the quantity of DNA used overall. We have examined 15 SNPs in the cholesteryl ester transfer protein (CETP) gene, a gene previously demonstrated to be associated with serum high-density lipoprotein cholesterol levels. The SNPs were amplified in two pools of DNA derived from groups of individuals with extremely high and extremely low serum high-density lipoprotein cholesterol levels, respectively. P values <0.05 were obtained for 14 SNPs, supporting the described association. Genotyping of the individual samples showed that the average margin of error in frequency estimate was approximately 4% when pools were used. These findings clearly demonstrate the potential of pooling techniques and their associated technologies as an initial screen in the search for genetic associations.

Clinical review 153: Lipodystrophy in human immunodeficiency virus-infected patients.

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV-infected patients. However, such therapy is associated with a lipodystrophy syndrome characterized by selective loss of sc fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen, and trunk. Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin resistance and its metabolic complications such as impaired glucose tolerance, diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been reported in some patients taking non-PI antiretroviral drugs. Other factors, such as duration of HIV infection, age, and gender, may also contribute to the risk of development of LDHIV. The molecular basis of LDHIV remains unknown. There is no specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and increasing physical activity may be beneficial in reducing fat accumulation as well as improving metabolic complications. Antihyperglycemic drugs may be used to treat diabetes. Management of dyslipidemia may require lipid-lowering drugs; however, the safety and efficacy of such intervention require further studies. Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and glucose intolerance, but whether reversal of lipodystrophy occurs remains unknown. Future research is needed to discover the biochemical and molecular markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral agents that are free of metabolic toxicity.

A low high density lipoprotein (HDL) level is associated with carotid artery intima-media thickness in asymptomatic members of low HDL families

Low serum high-density lipoprotein cholesterol (HDL-C) is a strong predictor of coronary heart disease (CHD). The aim of the present study was to evaluate the metabolic parameters predicting the atherosclerotic changes in asymptomatic members of low HDL-C families. We performed carotid B-mode ultrasonography with intima-media thickness (IMT) measurement for 89 asymptomatic members of Finnish low HDL-C families. The family members were categorized as affected or unaffected according to the 10th age-gender specific HDL-C percentile. In the affected group, the most marked decrease of HDL subclasses was observed for HDL 2-C when compared with the unaffected (109% difference). In the partial correlation analyses, age and gender showed significant correlations with the mean IMT (for age, r=0.880, P<0.001, and for gender, r=−0.361, P=0.018). Importantly, HDL-C and HDL 2-C were significantly inversely related to the mean carotid IMT, also after correction for age (for HDL-C, r=−0.186, P=0.043, for HDL 2-C, r=−0.208, P=0.029, when adjusted for age). The correlation for HDL-C was significant also when adjusted for gender. In conclusion, low HDL-C is associated with increased carotid artery IMT in asymptomatic members of low HDL-C families.

Pharmacologic therapy of lipid disorders in the elderly.

Older men and women with coronary artery disease, prior stroke, peripheral arterial disease, and extracranial carotid arterial disease with a serum low-density lipoprotein (LDL) cholesterol > 125 mg/dL despite diet should be treated with lipid-lowering drug therapy, preferably with statins, to reduce the serum LDL cholesterol to < 100 mg/dL. If statin drug therapy does not lower the serum LDL cholesterol to < 100 mg/dL in older persons with coronary artery disease, a bile acid binding resin, such as cholestyramine, should be added, since this drug does not increase the incidence of myositis in persons taking statins. The physician should use statins to treat older persons without atherosclerotic cardiovascular disease with a serum LDL cholesterol > or = 160 mg/dL plus one major risk factor, or a serum LDL cholesterol greater than or equal to 130 mg/dL plus a serum high-density lipoprotein (HDL) cholesterol < 50 mg/dL. Gemfibrozil may be useful in reducing the incidence of coronary events in persons with coronary artery disease whose primary lipid abnormality is a low serum HDL cholesterol level. There are no good data supporting treatment of hypertriglyceridemia unassociated with increased LDL cholesterol or decreased HDL cholesterol for prevention of cardiovascular disease.

Current status of coronary risk factors among rural Malays in Malaysia.

Coronary heart disease (CHD) is the leading cause of death in Malaysia, despite its status as a developing country. The rural population is thought to be at low risk. To investigate the prevalence of risk factors and global risk profile among rural Malays in Malaysia. We studied 609 rural Malay subjects (346 females, 263 males; age range 30-65 years). Blood pressure (BP), body mass index (BMI), waist-hip ratio (WHR), smoking habits and family history of premature CHD were documented. Fasting blood samples were analysed for serum lipids, lipoprotein (a), plasma glucose and fibrinogen. Oral glucose tolerance tests were performed using 75 g anhydrous glucose. The prevalence of hypercholesterolaemia for total cholesterol concentrations of > or = 5.2, > or =6.5 and > or =7.8 mmol/l were 67.3, 30.5 and 11.8% respectively. There was a high prevalence of low serum high-density lipoprotein cholesterol (13.1%), hypertension (30.3%), smokers (24.4%), diabetes (6.4%), impaired fasting glucose or glucose tolerance (13.9%), overweight or obesity (44.7%) and increased WHR (48.5%). Global risk assessment showed that 67.3% of the study population were at risk, with 15.9, 18.9 and 32.5% in the mild, moderate and high risk categories respectively. Prevalence of risk factors was high in the rural population. Global risk assessment showed a high-risk profile with two-thirds being at risk, and one-third being categorized into the high-risk group. Although rural communities were considered at low risk of developing CHD, this is changing fast, possibly due to the rapid socio-economic development, in addition to underlying genetic predisposition.

Incidence of new coronary events in older persons with prior myocardial infarction and serum low-density lipoprotein cholesterol ≥125 mg/dl treated with statins versus no lipid-lowering drug

O lder persons with hypercholesterolemia or increased serum low-density lipoprotein (LDL) or low serum high-density lipoprotein (HDL) cholesterol levels are at increased risk for new coronary events. Older persons with coronary artery disease (CAD) and elevated serum LDL cholesterol treated with simvastatin or pravastatin had a significant reduction in new coronary events. We are reporting data from an observational study investigating the effects of statins on the incidence of new coronary events in older men and women with prior myocardial infarction and a serum LDL cholesterol 125 mg/dl followed prospectively for the incidence of new coronary events. • • • Four hundred eighty-eight men and 922 women, mean age 81 9 years (range 60 to 100), with prior myocardial infarction and a serum LDL cholesterol 125 mg/dl treated with a statin or with no lipidlowering drug were followed prospectively in a longterm health care facility for the incidence of new coronary events. Persons were considered to have prior myocardial infarction if they had a documented clinical history of myocardial infarction or electrocardiographic evidence of Q-wave myocardial infarction. New coronary events were diagnosed if the person developed nonfatal or fatal myocardial infarction or sudden coronary death as previously described. Systemic hypertension was diagnosed according to the criteria of the Sixth Joint National Committee Report on the Detection, Evaluation, and Treatment of Hypertension. All persons with hypertension were treated with antihypertensive therapy. Diabetes mellitus was diagnosed according to the American Diabetes Association’s new criteria. Measurements of fasting serum lipids were obtained in all persons after a 12to 14-hour overnight fast at baseline, after 1 month of therapy, and every 6 months during the study. A serum LDL cholesterol 125 mg/dl was considered elevated. A serum HDL cholesterol 35 mg/dl was considered decreased. A serum triglyceride level 190 mg/dl was considered increased. A person was considered obese if the body mass index was 30 kg/m. The full-time staff physicians involved in the study treated 679 of 1,410 persons (48%) with a statin and 731 (52%) with no lipid-lowering drug. The attitude of different physicians toward treating hypercholesterolemia in older persons with prior myocardial infarction determined whether statins were prescribed. Persons were followed until the time of a new coronary event, death, or cutoff date analysis of data. Follow-up was 36 21 months (range 1 to 133). Chi-square tests were used to analyze dichotomous variables and Student’s t tests for continuous variables (Tables 1 to 4). Table 5 lists the prognostic variables for new coronary events and their regression coefficients in the stepwise Cox regression model. The Cochran-Armitage test was used to examine if there was a trend in the reduction of new coronary events in persons treated with statins as the last level of serum LDL cholesterol decreased (Table 6). Table 1 lists baseline characteristics of those treated with statins versus no lipid-lowering drugs and lists levels of statistical significance. Table 2 lists the baseline and last follow-up serum lipids in persons treated with statins versus no lipid-lowering drugs and lists levels of statistical significance. Table 3 shows the incidence of new coronary events in persons treated with statins versus no lipid-lowering drugs and lists the level of statistical significance. Table 5 shows the prognostic variables for new coronary events and their regression coefficients in the stepwise Cox regression model. Table 4 shows the incidence of new coronary events in persons treated with statins versus no lipid-lowering drugs for the age groups of 60 to 70, 71 to 80, 81 to 90, and 91 to 100 years, and lists levels of statistical significance. Table 6 shows the incidence of new coronary events in persons treated with statins From the Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, New York; and the Division of Clinical Epidemiology, University of Texas Medical School at Houston, Houston, Texas. Dr. Aronow’s address is: Department of Medicine, Westchester Medical Center/New York Medical College, 23 Pebble Way, New Rochelle, New York 10804. Manuscript received July 30, 2001; revised manuscript received and accepted September 4, 2001. TABLE 1 Baseline Characteristics of Persons With Prior Myocardial Infarction and Elevated Serum LDL Cholesterol Treated With Statins Versus No Lipid-Lowering Drug

Hyperglycemia-induced production of acute phase reactants in adipose tissue.

Chronic elevation of systemic levels of acute phase reactants and inflammatory cytokines found in patients with diabetes and the often-associated metabolic syndrome X (hypertriglyceridemia, low serum high density lipoprotein cholesterol, hypertension, and accelerated atherosclerosis) may be responsible for the increased incidence of cardiovascular problems in this population. Here we examine the contribution of adipose tissue to the systemic elevation of acute phase reactants associated with chronic hyperglycemia. We demonstrate that adipose tissue expresses a number of acute phase reactants at high levels, including serum amyloid A3 (SAA3), alphal-acid glycoprotein, the lipocalin 24p3 as well as plasminogen activator inhibitor-1 (PAI-1). Additionally, we show SAA3 is expressed at low levels under normal conditions but in the diabetic state is dramatically up-regulated in adipose tissue while down-regulated in liver. Furthermore, pro-inflammatory stimuli and high glucose can lead to the induction of SAA3 in adipose tissue in vivo as well as in the 3T3-L1 adipocyte cell line. Adipose tissue may therefore play a major role in the pathogenic sequelae of Type II diabetes, in particular the cardiovascular problems associated with prolonged hyperglycemia.

Endothelial dysfunction in resistance arteries is related to high blood pressure and circulating low density lipoproteins in previously treated hypertension

Background: Peripheral endothelial dysfunction has been demonstrated in hypertension. However, its relationship to blood pressure (BP) load, vascular structure, and metabolic disturbances in patients with long-standing, previously treated hypertension is unclear. Methods: A total of 41 patients with stage I to III essential hypertension and electrocardiographic left ventricular hypertrophy were studied. After 2 to 3 weeks of placebo treatment we measured nitroprusside-induced relaxation (NIR), acetylcholine-induced relaxation (AIR), and media:lumen ratio in isolated, subcutaneous resistance arteries by myography, as well as 24-h ambulatory BP, and serum lipids. Results: Maximal AIR correlated negatively with median 24-h diastolic BP (r = −0.42, P = .01), and sensitivity to AIR correlated negatively with serum low density lipoprotein (LDL) (r = −0.36, P < .05). In multiple regression analyses, sensitivity to AIR correlated negatively with serum LDL (β = −0.33) independently of maximal NIR (β = 0.41) (adjusted R 2 = 0.26, P < .01). Maximal acetylcholine-induced relaxation correlated negatively with median 24-h diastolic BP (β = −0.38) independently of maximal NIR (β = 0.45) (adjusted R 2 = 0.32, P < .001). Acetylcholine-induced relaxation was not significantly related to diabetes or to media:lumen ratio (r = −0.26, NS). Conclusions: High diastolic BP and high serum LDL were associated with impaired maximal AIR and reduced sensitivity to AIR, respectively, independently of smooth muscle cell responsiveness to nitroprusside. This indicated decreasing endothelial function in small resistance arteries with increasing BP and increasing LDL in hypertension. Endothelial function was not significantly related to vascular structure of the resistance arteries or to diabetes in these patients with long-standing hypertension.

Prevalence of and risk factors for abdominal aortic aneurysms in a population-based study : The Tromsø Study.

In a population-based study of 6,386 men and women aged 25--84 years in Tromsø, Norway, in 1994--1995, the authors assessed the age- and sex-specific distribution of the abdominal aortic diameter and the prevalence of and risk factors for abdominal aortic aneurysm. Renal and infrarenal aortic diameters were measured with ultrasound. The mean infrarenal aortic diameter increased with age. The increase was more pronounced in men than in women. The age-related increase in the median diameter was less than that in the mean diameter. An aneurysm was present in 263 (8.9%) men and 74 (2.2%) women (p < 0.001). The prevalence of abdominal aortic aneurysm increased with age. No person aged less than 48 years was found with an abdominal aortic aneurysm. Persons who had smoked for more than 40 years had an odds ratio of 8.0 for abdominal aortic aneurysm (95% confidence interval: 5.0, 12.6) compared with never smokers. Low serum high density lipoprotein cholesterol was associated with an increased risk for abdominal aortic aneurysm. Other factors associated with abdominal aortic aneurysm were a high level of plasma fibrinogen and a low blood platelet count. Antihypertensive medication (ever use) was significantly associated with abdominal aortic aneurysm, but high systolic blood pressure was a risk factor in women only. This study indicates that risk factors for atherosclerosis are also associated with increased risk for abdominal aortic aneurysm.

Hypophosphataemia: cause of the disturbed metabolism in the metabolic syndrome

The clustering of risk factors for cardiovascular disease (CVD) and non-insulin-dependent diabetes mellitus (NIDDM) in obese patients may be attributable to a disturbed metabolism caused by hypophosphataemia. A low serum phosphate (S-P) level may be a limiting factor for glucose metabolism and may account for hyperglycaemia, with an increased risk of NIDDM and hypertension and consequent increased risk of stroke. Low S-HDL levels, known to exist in the metabolic syndrome, as well as high serum triglycerides may also have been the results of phosphate depletion. The hypothesis presents a new serious disturbance which accounts for the dyslipidaemia, hyperglycaemia and the hypertension in metabolic syndrome. The proposed causal relationship between low S-P and the clustering of risk factors is based on results from a cross-sectional study of obese patients, where low S-P was associated with high body mass index (BMI), high blood glucose (B-glu), high systolic blood pressure (SBP), high diastolic blood pressure (DBP), but low serum high density lipoprotein (S-HDL) and serum magnesium (S-Mg) levels. Knowledge from experimental and clinical studies on hypophosphataemia and/or phosphate depletion are referred to when discussing the hypothesis.