Dyslipidemias and Atherosclerotic Thrombotic Disease

Article 1. Familial combined hypercholesterolemia (FCH) is the most common inherited hyperlipidemia complicated by premature atherothrombotic complications, but its genetic and metabolic basis has not been elucidated. FCH, according to the traditional criteria of total cholesterol (TC) and/or triglyceride (TG), is heterogeneous. The diagnosis of FCH on the basis of TC and TG levels is inconsistent and insufficient. Other major characteristics of FCH include elevated apolipoprotein B (apoB), the preponderance of small dense low-density lipoprotein (sdLDL), and decreased high-density lipoprotein (HDL). FCH is associated with insulin resistance and visceral obesity, indicating similarities and/or overlap with the metabolic syndrome. Insulin resistance and obesity do not fully account for elevated apoB. The clinical and laboratory phenotypes of FCH are influenced by environmental factors including lifestyle, diet, and exercise. TG is the strongest and apoB the second most important predictor of FCH. The diagnosis of FCH is best established by age- and gender-adjusted elevated apoB levels combined with TC and TG. A not yet identified major gene affecting free fatty acid (FFA) metabolism in adipose tissue influences apoB, TG levels, and insulin resistance. The presence of sdLDL variants of FCH might result from the combination of a dominant major gene and several modifier genes influencing plasma lipid levels.

Article 2. Autosomal recessive hypercholesterolemia (ARH) is a phenotype copy of classical familial hypercholesterolemia (FH) and premature atherothrombosis caused by LDL receptor mutations, but less severe and more responsive to lipid-lowering therapy. Most of the patients with ARH are homozygous for the same allele from consanguineous parents or heterozygous for two different alleles of the ARH gene. ARH protein is clearly required for normal LDL receptor-mediated endocytosis of LDL in hepatocytes. All but one of the described ARH mutations are nonsense mutations that fail to produce ARH protein. Missense mutations do not appear to influence plasma ARH levels (polymorphism). ARH is required for normal LDL receptor function. Homozygosity or double heterozygosity for ARH nonsense mutations is featured by elevated LDL but to a lesser extent as in FH. Heterozygotes for ARH nonsense mutations have normal LDL levels. In contrast to those with homozygous FH, the majority of homozygous ARH patients respond well to lipid-lowering drug therapy.

Article 3. Three polymorphisms of apoE can be distinguished and designated as apoE2, apoE3, and apoE4 with allele frequencies of ∼0.10, 0.75, and 015, respectively. ApoE2 upregulates LDL receptor, enhances LDL clearance, and impairs conversion of apoE2 containing very-low-density lipoprotein (VLDL) via intermediate-density lipoprotein (IDL) to LDL. Subjects with the apoE2 allele have high levels of apoE2 and low levels of TC, LDL, and apoB, whereas apoE4 is associated with the opposite. ApoE4 carriers are at higher risk of Alzheimer's disease and apoE4 carriers in male myocardial survivors have a twofold higher mortality risk compared with non-apoE4 carriers.

Homozygosity of apoE2 can result in familial recessive dysbetalipoproteinemia (FD), also designated as type III hyperlipidemia or broad β or remnant disease. Rare apoE variants result in FD with a dominant inheritance (apoE3-Leiden, aApoE2[Lys146Gln]). FD is characterized by increased TC, TG, and IDL, decreased LDL, and decreased HDL but to a lesser extent and the presence of β-VLDL on agarose gel electrophoresis. Homozygosity for apoE2 causes symptomatic FD, characterized by peripheral artery disease (PAD) as frequently as coronary artery disease (CAD), in less than 20% of adults. FD rarely occurs before adulthood and is more prevalent in men than in women, who do not express atherothrombotic disease until menopause. The asymptomatic apoE2 homozygotes are normolipidemic with β-VLDL in their plasma. Other factors such as insulin resistance, gender, age, and LPL mutations contribute to the phenotypic expression of FD. FD patients are usually very responsive to statin and lifestyle diet interventions.

Article 4. ApoB is the structural moiety of LDL particles and acts as a ligand in the cellular binding and uptake of LDL. Normal receptor binding between LDL and apoB is positioned in the carboxy terminal apoB protein created by amino acid residues 3359-3369. Absence of the arginines R3480, R3500, and R3531 in the terminal apoB gene hampers cellular uptake of LDL and causes familial defective apolipoprotein B (FDB). Heterozygous FDB is characterized by increased TC and LDL but to a lesser extent than in heterozygous FH. FH and FDB are best identified by increased TC and LDL; however, many patients will be missed by lipid analysis alone. Both disorders therefore should be actively pursued to identify mutation carriers for targeted and timely intervention for the primary prevention of coronary artery disease (CAD). FDB patients have substantially less increased TC and LDL levels and CAD risk compared with FH heterozygotes.

Article 5. This article deals with procedures for assessing the clinical relevance of genetic variation related to cardiovascular disease by adding mortality analysis to genetic association studies. Various methods of genetic association with cardiovascular disease and mortality are reviewed, including selecting functional candidate genes, the parent-offspring method, and calculating a standardized mortality ratio using data on the frequency of SNPs and the death rates of the general population. The feasibility of such analyses and the pros and cons of these methods are discussed.

Article 6. In 570 genotyped FH cases, apoE and apoB account for only 3.9% and 2.7% variation in plasma LDL-cholesterol (LDL-C). In Sardinian young adults with β-thalassemia major, the levels of TC, LDL-C, HDL-C, and apoB are reduced by 30 to 50% whereas plasma TG is increased by 35% compared with matched controls. In thalassemia minor (β-thalassemia carrier) this reduction is usually in the range of 6 to 12% to values found in controls. The frequency of β-thalassemia carrier in 359 Italian men with myocardial infarction was much lower (2%) than in matched controls (12%). These data suggest that the protective effect of β-thalassemia trait against CAD is related to lower plasma cholesterol levels as well as reduced blood viscosity caused by anemia and microcytosis. After adjustment for age, gender, body mass index, and apoE levels in a large series of FH heterozygotes, plasma TC and LDL-C levels in β-thalassemia carriers were lower, 27 and 30%, respectively, than in noncarriers of β-thalassemia, whereas TG levels were similar in the two groups. The mechanisms underlying the LDL-C lowering effect in patients with β-thalassemia major, intermedia, and minor remain elusive.

Article 7. Alzheimer's disease (AD) is a common cause of dementia in elderly people with a prevalence of more than 5% above the age of 65 and ∼25% in those older than 85 years. Early-onset familial AD is quite rare and constitutes ∼1-2% of all AD cases. Four genes have been associated with an inherited susceptibility to AD: presenilin 1 (PS1), presenilin 2 (PS2), amyloid precursor protein (APP), and apoE4 on chromosomes 14, 1, 21, and 19, respectively. ApoE4 may account for ∼40% of late-onset AD.

Article 8. The vascular risk of patients with cerebrovascular atherosclerotic disease differs from that in coronary artery disease. Both diastolic blood pressure (DBP) and systolic blood pressure (SBP) are related to cerebrovascular accidents including transient ischemic attacks (TIAs) and stroke. The lowest risk for stroke is associated with a DBP below 80 mm Hg and SBP below 142 mm Hg. The administration of aspirin had no effect on stroke in treated hypertensive patients. The benefit of angiotensin-converting enzyme (ACE) inhibition (ramipril) in terms of cardiovascular and stroke risk reduction was more than relative to blood pressure reduction only, indicating an additional vascular or renal effect of ACE inhibition in diabetic patients. An ACE inhibitor (perindopril) and a diuretic agent versus no diuretic agent reduced blood pressure by 12/5 and stroke risk by 45% in patients with a history of TIA or stroke. An angiotensin II type 1 receptor antagonist (losartan) versus a β-blocker (atenolol) induced a similar reduction in SBP and DBP, but the stroke outcome was in favor of losartan with an additional relative risk reduction of 24%.

Thromboembolic stroke increases with worsening of glucose tolerance from impaired to overt non-insulin-dependent diabetes mellitus (NIDDM) independently of other well-known CAD risk factors. Diabetic patients have more frequent hypertension and stroke and increased stroke mortality compared with nondiabetics. NIDDM, its metabolic control, and duration of diabetes are important predictors of stroke in elderly patients, particularly women.

This article proposes a classification that distinguishes five different clinical subtypes of ischemic stroke. (1) Large-artery atherosclerosis (LAAS) is associated with hypercholesterolemia and smoking. (2) Cardioembolic infarct (CEI) is associated with atrial fibrillation, hypertension, and smoking. (3) Lacunar infarct (LAC) is associated with diabetes, hypertension, and history of TIA. (4) Stroke of other determined origin (ODE) is rare in diabetes. (5) Stroke of undetermined etiology (UDE) is rare in hypertension.

Insulin resistance as a main component of the metabolic syndrome (MS) is associated with increased risk of stroke, which was independent of other risk factors, particularly obesity. Increase of body mass index (BMI) and weight gain during long-term follow-up of more than 15 years constitute an independent risk factor for ischemic stroke. Microalbuminuria is prevalent in patients with recent stroke (29%), which merits further examination as a potential marker of stroke. Microalbuminuria can be used as an independent risk factor for stroke in NIDDM patients. The relation between increased TC and CAD is well established and strong, and the association of increased TC and stroke is less well studied and relatively weak. Several studies have shown that statin-induced reduction of TC and LDL-cholesterol is associated with a 20 to 35% relative risk reduction for stroke. Nonvalvular atrial fibrillation (AF) is associated with a four- to sixfold increased relative risk of stroke, and this risk is reduced by 60 to 70% by therapy with vitamin K antagonist. Older age, hypertension, prior cerebral ischemia, diabetes, and left ventricular dystrophy are well-recognized factors for stroke in AF. The relative risk for stroke of cigarette smoking as compared with nonsmoking depends on the population studied: 3 to 4 in Western countries and 1.6 in a Japanese study. The benefit of stopping smoking is seen within 5 years. C-reactive protein predicts further ischemic events after a first episode of TIA or stroke.

Article 9. New strategies in the treatment of dyslipidemias clearly document that aggressive treatment reaching target values is far better than usual care in adult and elderly patients for secondary prevention and treatment of vascular risk and disease. Target values of plasma lipid levels are TC 5.0 (highest risk 4.5), LDL.C 3.0 (highest risk 2.6), TG less than 1.7, and HDL more than 1.0 (optimum above 1.6) mmol/L. Atorvastatin, rosuvastatin, and pitavastatin are more potent lipid-lowering agents than simvastatin and pravastatin. Lipid lowering on top of blood pressure-lowering therapy is better than blood pressure control alone in hypertensive patients. The combination of a potent statin and ezetimibe (a selective cholesterol resorption inhibitor) is of advantage in patients with pronounced hyperlipidemias such as FH, ARH and FCH. The combination of a statin and CETP inhibitor or a combination of ezetimibe and fibrates (PPAR-α antagonists) may be of advantage in correcting the lipid profile and reducing cardiovascular risk in patients with the metabolic syndrome and diabetes.

I would like to express my gratitude and appreciation to Dr. Joep Defesche and sincere thanks to all authors for the very interesting articles on laboratory diagnosis and molecular biology of dyslipidemias and additional articles on cerebrovascular manifestations and lipid-lowering therapy of atherosclerotic thrombotic disease.