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Familial hypercholesterolemia (FH) is an autosomal codominant lipoprotein disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) and high risk of premature atherosclerotic cardiovascular disease. Definitions for FH rely on complex algorithms that are on the basis of levels of total or LDL-C, clinical features, family history, and DNA analysis that are often difficult to obtain. We propose a novel simplified definition for FH. Definite FH includes: (1) elevated LDL-C (≥ 8.50 mmol/L); or (2) LDL-C ≥ 5.0 mmol/L (for age 40 years or older; ≥ 4.0 mmol/L if age younger than 18 years; and ≥ 4.5 mmol/L if age is between 18 and 39 years) when associated with at least 1 of: (1) tendon xanthomas; or (2) causal DNA mutation in the LDLR, APOB, or PCSK9 genes in the proband or first-degree relative. Probable FH is defined as subjects with an elevated LDL-C (≥ 5.0 mmol/L) and the presence of premature atherosclerotic cardiovascular disease in the patient or a first-degree relative or an elevated LDL-C in a first-degree relative. LDL-C cut points were determined from a large database comprising > 3.3 million subjects. To compare the proposed definition with currently used algorithms (ie, the Simon Broome Register and Dutch Lipid Clinic Network), we performed concordance analyses in 5987 individuals from Canada. The new FH definition showed very good agreement compared with the Simon Broome Register and Dutch Lipid Clinic Network criteria (κ = 0.969 and 0.966, respectively). In conclusion, the proposed FH definition has diagnostic performance comparable to existing criteria, but adapted to the Canadian population, and will facilitate the diagnosis of FH patients., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

We describe a patient with markedly elevated lipoprotein(a) (Lp(a)) without any other lipid abnormalities. After a myocardial infarction, she was treated with combination of extended-release niacin and statin. An 88% reduction in Lp(a) was observed during 5 years of treatment, which is much better response than usually reported., (Copyright © 2014 National Lipid Association. Published by Elsevier Inc. All rights reserved.)

Until recently, coronary artery disease (CAD) was the leading cause of death in the developed countries. Its remarkable decline can be attributed to our knowledge of the major risk factors identified by several studies resulting in better prevention and treatment. Of the major risk factors, the ratio of apolipoprotein (apo) B/apo A1 followed by smoking, diabetes, and hypertension are the most important. A number of risk scores for men and women are now available to estimate the likelihood of development of CAD. However, because of the risk of CAD differs in various populations, some of the algorithms are more appropriate for some countries but not suitable for others. These risk assessment algorithms differ in the parameters they use. All the risk scores have some limitations such as different study populations; the age of the study is also different, and number of points awarded for age categories also differs among the various algorithms. In an effort to further improve the risk prediction, a number of biomarkers have been studied. In addition to plasma lipids, a lot of interest has focused on apo measurements; particularly of apo B. Another valuable biomarker is lipoprotein (a) [Lp(a)]. Lp(a) is not only atherogenic as low-density lipoprotein (LDL) but also prothrombotic, and several studies indicate that Lp(a) is an independent risk factor for CAD. The lipid profile provides a framework for appropriate management. This includes therapeutic lifestyle changes and medications. Lifestyle interventions are the cornerstone of CAD prevention strategies and are the first step in risk factor management. Of particular importance are smoking cessation, achievement and maintenance of ideal body weight, regular exercise, reduction in the intake of saturated fat and sugars, and decreasing level of stress. Of medications, lipid-lowering, anti-hypertensive, and anti-coagulant can be effectively used. The current strategies for risk assessment and prevention have been very successful contributing to the more than 50% decrease in CAD mortality over the last 20 years. Thus, in Canada, cardiovascular disease is no longer the leading cause of death., (Crown Copyright © 2013. Published by Elsevier Inc. All rights reserved.)

Background: To evaluate the frequency of positive coronary arteries calcium (CAC) scores in a unique population of asymptomatic first degree relatives (FDRs) of patients with angiographically confirmed early onset of coronary artery disease (CAD) and to assess their association with carotid ultrasound findings and other cardiovascular risk factors., Method and Results: We scanned, using 64-slice multi-detector computed tomography, 57 asymptomatic FDRs (47 ± 9 years old; 44% male, 56% female), out of the 111 FDRs previously phenotyped for cardiovascular (CV) risk factors. The controls were 616 individuals (57 ± 10 years old; 76% male, 24% female) with no family history of cardiovascular disease, chest pain or diabetes selected out of the 3500 subjects scanned between 2002 and 2007. FDRs had higher risk of abnormal CAC scores compared to controls; odds ratio (OR) for the 75th percentile was 1.96 (95% CI 1.04-3.67, p < 0.05)., Conclusion: The frequency of abnormal CAC scores is two-fold higher in asymptomatic FDRs than in controls. CAC scan provides additional information on CV risk assessment in asymptomatic FDRs, particularly for those in the intermediate risk category., Clinical Trial Registration: NCT00387595.

Background: First-degree relatives (FDRs) of subjects with early onset of coronary heart disease (CHD) have higher risk of developing cardiovascular disease. We verified early CHD by angiography in index patients and extensively phenotyped their FDRs to investigate the relationship of traditional and nontraditional cardiovascular risk factors to carotid ultrasound measures of subclinical atherosclerosis., Methods and Results: B-mode carotid ultrasound was used to assess the combined intimamedia thickness and plaque burden in 111 FDRs (65 men, 44.4 +/- 11 and 46 women, 44.7 +/- 13 years old) of 82 index patients (men <50 and women <60 years of age at the time of the event). The biochemical and anthropometrical characteristics of the FDRs were compared with those of healthy controls matched for sex, age, ethnicity, and body mass index. First-degree relatives had increased average total thickness (a combined measure of intimamedia thickness and plaque) compared to controls (0.76 mm, interquartile range [IQR] 0.69-1.01 vs 0.69 mm, IQR 0.60-0.88, P < .001) even after adjusting for age, total cholesterol-to-high-density lipoprotein cholesterol ratio, systolic blood pressure, waist circumference, and smoking (beta = 0.143, P < .05). No differences were observed in average intimamedia thickness measurements alone. Of the nontraditional risk factors, only plasma homocysteine was higher in FDRs then in controls (9.6 mg/L, IQR 8.0-11.1 versus 7.5 mg/L, IQR 6.4-8.7, P < .001), after adjusting for all other confounding variables., Conclusion: First-degree relatives of patients with angiographically confirmed CHD have higher burden of subclinical atherosclerosis even when considered in the context of traditional risk factors. Noninvasive assessment of carotid artery plaques and intimamedia thickness and plasma homocysteine measurements may be useful in such patients.

The aim of our study was to evaluate the relationship of adiponectin to soluble forms of vascular cell adhesion molecule-1 (sVCAM-1) and intercellular cell adhesion molecule-1 (sICAM-1) in patients with cardiovascular disease or dyslipidemia. Two hundred and sixty-four patients (134 men/130 women, mean age 43.8+/-14.8/46.0+/-14.9 years) of Lipid Center, University Hospital Olomouc, off hypolipidemic therapy for at least 6 weeks, participated in the study. In multiple regression analysis, adiponectin was independently positively associated with serum HDL-cholesterol (p<0.0001) and sVCAM-1 (p<0.0001), female gender (p<0.0001) and negatively with hs-CRP (p=0.014). Serum concentration of adiponectin and sICAM-1 did not correlate but sICAM-1 was independently, positively associated with sVCAM-1 (p<0.0001) and negatively with markers of insulin resistance and inflammation, namely atherogenic index log[triglycerides/HDL-cholesterol] (p<0.0001), hs-CRP (p<0.001) and HOMA (p<0.05). Positive association of adiponectin with HDL-C and negative association with hs-CRP indicate anti-atherogenic properties of adiponectin. The finding of the positive association of adiponectin with sVCAM-1 in patients at risk is unexpected. We hypothesize that adiponectin may be involved (directly or indirectly) in shedding of ectodomains of VCAM-1 from endothelial surface and in this way down-regulates their effects. This process may be protective in the initial stages of atherosclerosis.

Purpose: Atherosclerosis contributes to cardiovascular mortality and morbidity even with aggressive lipid management. Our objective is to determine whether a combined pharmacological and lifestyle intervention can improve atherosclerosis., Methods: We conducted a 2-year observational study at a specialized clinic in a tertiary care hospital. One hundred fifty-six subjects with coronary disease were enrolled in an intensive pharmacological management and lifestyle measures (including counseling and exercise training) program designed to reach specific targets. The main outcome measures were carotid intima media thickness and plaque area; brachial artery flow-mediated dilation; nitroglycerin-mediated dilation; flow-mediated dilation-nitroglycerin-mediated dilation ratio; laboratory parameters including lipids, glucose, creatinine, and homocysteine; and physical fitness., Results: At completion, there were improvements in lipids and physical fitness. There were no overall changes in flow-mediated dilation, nitroglycerin-mediated dilation, or carotid intima media thickness in the entire cohort. However, multivariate logistic regression showed that dietary and exercise variables, such as increasing fiber intake and reducing body weight and body fat percentage, were independent predictors of improvements in endothelial function and carotid plaque burden., Conclusions: Even in the setting of intensive pharmacological therapy, lifestyle interventions, including exercise training and dietary changes, are important determinants of improved endothelial function and atherosclerosis.

There is abundant evidence that the risk of atherosclerotic vascular disease is directly related to plasma cholesterol levels. Accordingly, all of the national and transnational screening and therapeutic guidelines are based on total or LDL cholesterol. This presumes that cholesterol is the most important lipoprotein-related proatherogenic risk variable. On the contrary, risk appears to be more directly related to the number of circulating atherogenic particles that contact and enter the arterial wall than to the measured concentration of cholesterol in these lipoprotein fractions. Each of the atherogenic lipoprotein particles contains a single molecule of apolipoprotein (apo) B and therefore the concentration of apo B provides a direct measure of the number of circulating atherogenic lipoproteins. Evidence from fundamental, epidemiological and clinical trial studies indicates that apo B is superior to any of the cholesterol indices to recognize those at increased risk of vascular disease and to judge the adequacy of lipid-lowering therapy. On the basis of this evidence, we believe that apo B should be included in all guidelines as an indicator of cardiovascular risk. In addition, the present target adopted by the Canadian guideline groups of an apo B <90 mg dL(-1) in high-risk patients should be reassessed in the light of the new clinical trial results and a new ultra-low target of <80 mg dL(-1) be considered. The evidence also indicates that the apo B/apo A-I ratio is superior to any of the conventional cholesterol ratios in patients without symptomatic vascular disease or diabetes to evaluate the lipoprotein-related risk of vascular disease.

The Diabetes Atherosclerosis Intervention Study (DAIS) examined the effects of fenofibrate or placebo on the progression of coronary artery disease (CAD) in 418 type 2 diabetic subjects with dyslipidemia. Fenofibrate use was associated with a 6% increase in high-density lipoprotein cholesterol, a 28% decrease in triglycerides, a 5% decrease in low-density lipoprotein cholesterol, and a 55% increase in plasma homocysteine (tHcy). The purpose of the present study was to determine whether this increase in tHcy in the fenofibrate group was associated with CAD progression or with clinical events. The increase in tHcy with fenofibrate (n = 207) was not related to changes in factors known to modulate tHcy levels (serum levels of Vitamin B(12), folate, or renal function). CAD was quantified by angiography at baseline and after a minimum of 3 years of therapy with fenofibrate or placebo. The primary end point was change in mean segment diameter (MSD), minimal lumen diameter, and percent stenosis. Baseline tHcy level was correlated with percent diameter stenosis (r = 0.111, p = 0.028). Baseline, but not end-of-study elevated tHcy levels, decreased the beneficial effect of fenofibrate. Unexpectedly, the final tHcy levels correlated negatively with CAD progression (r = -0.111, p = 0.031) in the overall group. In the fenofibrate group, there was no significant correlation between tHcy and minimal lumen diameter (r = -0.135, p = 0.069), or percent stenosis. An increase in tHcy levels was not correlated with adverse clinical events in the fenofibrate group. This analysis of the the DAIS reveals that the fenofibrate-mediated increase in tHcy levels does not attenuate the beneficial effects of fenofibrate on CAD progression or clinical events.

The high-density lipoprotein (HDL)-Atherosclerosis Treatment Study showed that simvastatin plus niacin (mean daily dose 13 mg and 2.4 g, respectively) halt angiographic atherosclerosis progression and reduce major clinical events by 60% in patients with coronary artery disease (CAD) who have low HDL, in comparison with placebos, over 3 years. How safe and well-tolerated is this combination? One hundred sixty patients with CAD, including 25 with diabetes mellitus, with mean low-density lipoprotein cholesterol of 128 mg/dl, HDL cholesterol of < or =35 mg/dl (mean 31), and mean triglycerides of 217 mg/dl were randomized to 4 factorial combinations of antioxidant vitamins or their placebos and simvastatin plus niacin or their placebos. Patients were examined monthly or bimonthly for 38 months; side effects (gastrointestinal upset, nausea, anorexia, vision, skin, and energy problems, or muscle aches) were directly queried and recorded. Aspartate aminotransferase, creatine phosphokinase (CPK), uric acid, homocysteine, and fasting glucose levels were regularly monitored. A safety monitor reviewed all side effects and adjusted drug dosages accordingly. Patients who received simvastatin plus niacin and those on placebo had similar frequencies of clinical or laboratory side effects: any degree of flushing (30% vs 23%, p = NS), symptoms of fatigue, nausea, and/or muscle aches (9% vs 5%, p = NS), aspartate aminotransferase (SGOT) > or =3 times upper limit of normal (3% vs 1%, p = NS), CPK > or =2 times upper limit of normal (3% vs 4%, p = NS), CPK > or =5 times upper limit of normal, new onset of uric acid > or =7.5 mg/dl (18% vs 15%, p = NS), and homocysteine > or =15 micromol/L (9% vs 4%, p = NS). Glycemic control among diabetics declined mildly in the simvastatin-niacin group but returned to pretreatment levels at 8 months and remained stable for rest of the study. This combination regimen was repeatedly described by 91% of treated patients and 86% of placebo subjects as "very easy" or "fairly easy" to take. Thus, the simvastatin plus niacin regimen is effective, safe, and well tolerated in patients with or without diabetes mellitus.

The objective of the study was to assess the association between plasma levels of lipoprotein(a) [Lp(a)] and the presence of angiographically defined coronary artery disease (aCAD). Patients (346 men and 184 women) undergoing selective coronary angiography (SCA) were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings and their age, body mass index (BMI), waist circumference, blood pressure, smoking, plasma total, LDL-, HDL-cholesterol (TC, LDL-C, HDL-C), triglycerides (TG), apolipoprotein B (apoB), Log(TG/HDL-C) and TC/HDL-C were determined. Concentration of plasma Lp(a) was estimated using the commercial solid phase two-side immunoradiometric assay of apolipoprotein apo(a). The plasma Lp(a) was significantly higher in both women and men with aCAD(+) compared to those with aCAD(-). While there was no significant difference in the Lp(a) level between men and women with aCAD(-) (median 138 vs. 145 units/l), the women with aCAD(+) had almost twice as high Lp(a) levels as men (median 442 vs. 274 units/l, p<0.001). Women with aCAD(+) had also significantly lower HDL cholesterol levels (1.09 vs. 1.20 mmol/l, p<0.05), higher triglycerides (1.82 vs. 1.46 mmol/l, p<0.05) and Log(TG/HDL-C) than women with aCAD(-). The differences in Lp(a) between positive and negative findings remained highly significant (p<0.001 in women, p<0.05 in men) after the adjustment for age, plasma HDL- and LDL-cholesterol and triglycerides in logistic regression analyses. In logistic regression model the Lp(a) and Log(TG/HDL-C) and smoking in women but smoking and age in men were the most powerful predictors of positive aCAD findings. Our findings suggest that Lp(a) is more strongly associated with aCAD+ in women than in men.

Background: Chest pain is a common complaint in patients with anorexia nervosa (AN). Of those who experience chest pain, about 20% meet the diagnostic criteria for typical or atypical angina., Methods: We compared the intima-medial thickness (IMT) of the carotid artery measured by ultrasound in AN with controls and found no difference., Results and Discussion: Although clinically relevant atherosclerosis can occur in patients with a normal IMT, there is a strong correlation between carotid IMT and coronary atherosclerosis. This suggests that an atherosclerotic origin of chest pain in AN patients is unlikely., (Copyright 2003 by Wiley Periodicals, Inc.)

Background: We examined the predictive value of various clinical and biochemical markers for angiographically defined coronary artery disease (aCAD). Specifically, we assessed the value of the ratio of plasma triglyceride (TGs) to HDL-cholesterol (HDL-C) and the fractional esterification rate of cholesterol in plasma depleted of apolipoprotein B (apoB)-containing lipoproteins (FER(HDL)), a functional marker of HDL and LDL particle size., Methods: Patients (788 men and 320 women) undergoing coronary angiography were classified into groups with positive [aCAD(+)] and negative [aCAD(-)] findings. Patient age, body mass index, waist circumference, blood pressure (BP), medications, drinking, smoking, exercise habits, and plasma total cholesterol (TC), LDL-cholesterol (LDL-C), HDL-unesterified cholesterol, HDL-C, TGs, FER(HDL), apoB, log(TG/HDL-C), and TC/HDL-C were assessed. Lipids and apoproteins were measured by standard laboratory procedures; FER(HDL) was determined by a radioassay., Results: Members of the aCAD(+) group were older and had a higher incidence of smoking and diabetes than those in the aCAD(-) group. The aCAD(+) group also had higher TG, apoB, FER(HDL), and log(TG/HDL-C) and lower HDL-C values. aCAD(+) women had greater waist circumference and higher plasma TC and TC/HDL-C. aCAD(+) men, but not women, had higher plasma LDL-C. In the multivariate logistic model, the significant predictors of the presence of aCAD(+) were FER(HDL), age, smoking, and diabetes. If only laboratory tests were included in the multivariate logistic model, FER(HDL) appeared as the sole predictor of aCAD(+). Log(TG/HDL-C) was an independent predictor when FER(HDL) was omitted from multivariate analysis., Conclusions: FER(HDL) was the best laboratory predictor of the presence of coronary atherosclerotic lesions.

A panel consisting of lipidologists, epidemiologists, cardiologists, internists, general practitioners, and public health and government representatives used the evidence-based approach to examine the rationale for a draft of recommendations for medical management of lipid disorders. The proposed recommendations deal with assessment of cardiovascular risk based on history, physical examination and laboratory findings; assessment of the fasting lipid profile; diagnosis and treatment of secondary risk factors; calculation of the 10-year risk of a cardiac event; initiation of lifestyle modifications in patients in whom low density lipoprotein cholesterol (LDL-C), total:high density lipoprotein cholesterol (HDL-C) ratio or triglycerides exceeds target values based on a patient's risk category; follow-up; treatment with drugs; and choices of drugs. In contrast to previous recommendations, there are new, considerably lower, cholesterol level targets for secondary prevention, with a less important emphasis on total cholesterol value than on LDL-C or total:HDL-C ratio and triglyceride levels, and an emphasis on determining the likelihood of a cardiac event by evaluating all relevant risk factors and sharpening the focus on nondrug treatment, which should result in treating a greater percentage of at-risk patients.

Evidence supports the idea that substantial benefits may derive from treatments that increase high density lipoprotein (HDL) cholesterol (HDL-C), apolipoprotein (apo) A-I, HDL2 (or 2b) or the size of HDL particles with, or without, apo A-II. HDL3 appears to be neutral in terms of coronary artery disease risk, and apo A-II appears to be adverse. Because HDL particles serve as antioxidants in vitro, the hypothesis that low HDL-C reflects an antioxidant deficiency state appears tenable. Based on these observations, a three-year angiographic study was proposed and received funding. Enrollment began in January 1995 and was completed in January 1997.

Two new important independent risk factors for coronary artery disease (CAD) have been identified: lipoprotein (a) [Lp(a)] and homocyst(e)ine. Both are associated with increased frequency of cardiovascular events, both coronary and peripheral. Measurement of these two factors should be considered in patients with symptomatic CAD, stroke, a strong family history (but low other conventional risk factors); in first degree relatives of those with very high Lp(a) or homocyst(e)ine levels; and in other individuals in whom the need for an aggressive treatment of metabolic risk factors is indicated. While treatment of high serum Lp(a) with drugs is difficult it appears from the epidemiological or clinical evidence that the additional risk due to Lp(a) can be drastically lowered by decreasing the patient's low density lipoprotein (LDL) cholesterol levels to below 3 mmol/L. The treatment of increased homocyst(e)ine can be easily accomplished by vitamin B6 or folic acid administration. Various analyses describing the value of positive tests for diagnosis of atherosclerosis indicate that overall risk evaluated by computer models from Framingham data, use of total: high density lipoprotein (HDL) cholesterol ratio and/or the National Cholesterol Education Program (NCEP) II guidelines are the best predictors of future cardiovascular events. The strategic aim for treatment regimens should be threefold: lower serum LDL cholesterol levels; decrease serum triglycerides (and triglyceride-rich lipoproteins); and increase HDL cholesterol. Niacin and statin drugs are the most cost effective means to achieve the former and niacin and fibrates to achieve the latter goal. Where target LDL cholesterol levels can be achieved with less expensive statin preparations their use may be economically advantageous.