Our purpose is to provide a framework for diagnosing the inherited causes of marked high-density lipoprotein (HDL) deficiency (HDL cholesterol levels <10 mg/dL in the absence of severe hypertriglyceridemia or liver disease) and to provide information about coronary heart disease (CHD) risk for such cases. Published articles in the literature on severe HDL deficiencies were used as sources. If apolipoprotein (Apo) A-I is not present in plasma, then three forms of ApoA-I deficiency, all with premature CHD,and normal low-density lipoprotein (LDL) cholesterol levels have been described: ApoA-I/C-III/A-IV deficiency with fat malabsorption, ApoA-I/C-III deficiency with planar xanthomas, and ApoA-I deficiency with planar and tubero-eruptive xanthomas (pictured in this review for the first time). If ApoA-I is present in plasma at a concentration <10 mg/dL, with LDL cholesterol that is about 50% of normal and mild hypertriglyceridemia, a possible diagnosis is Tangier disease due to mutations at the adenosine triphosphate binding cassette protein A1 (ABCA1) gene locus. These patients may develop premature CHD and peripheral neuropathy, and have evidence of cholesteryl ester-laden macrophages in their liver, spleen, tonsils, and Schwann cells, as well as other tissues. The third form of severe HDL deficiency is characterized by plasma ApoA-I levels <40 mg/dL, moderate hypertriglyceridemia, and decreased LDL cholesterol, and the finding that most of the cholesterol in plasma is in the free rather than the esterified form, due to a deficiency in lecithin:cholesterol acyltransferase activity. These patients have marked corneal opacification and splenomegaly, and are at increased risk of developing renal failure, but have no clear evidence of premature CHD. Marked HDL deficiency has different etiologies and is generally associated with early CHD risk.

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Patients with FH had an increased burden of coronary atherosclerosis by CTCA. The burden of atherosclerosis and individual plaque subtypes differed with the presence of other associated risk factors, with age and cholesterol being most important. A coronary calcium score of zero ruled out obstructive disease in this higher risk population.

Our aim was to characterize HDL subspecies and fat-soluble vitamin levels in a kindred with familial apolipoprotein A-I (apoA-I) deficiency. Sequencing of the APOA1 gene revealed a nonsense mutation at codon 22, Q[22]X, with two documented homozygotes, eight heterozygotes, and two normal subjects in the kindred. Homozygotes presented markedly decreased HDL cholesterol levels, undetectable plasma apoA-1, tuboeruptive and planar xanthomas, mild corneal arcus and opacification, and severe premature coronary artery disease. In both homozygotes, analysis of HDL particles by two-dimensional gel electrophoresis revealed undetectable apoA-I, decreased amounts of small a-3 migrating apoA-II particles, and only modestly decreased normal amounts of slow a migrating apoA-IV-and apoEcontaining HDL, while in the eight heterozygotes, there was loss of large a-1 HDL particles. There were no significant decreases in plasma fat-soluble vitamin levels noted in either homozygotes or heterozygotes compared with normal control subjects. Our data indicate that isolated apoA-I deficiency results in marked HDL deficiency with very low apoA-II a-3 HDL particles, modest reductions in the separate and distinct plasma apoA-IV and apoE HDL particles, tuboeruptive xanthomas, premature coronary atherosclerosis, and no evidence of fat malabsorption. Decreased plasma HDL cholesterol levels (,40 mg/dl in men and ,50 mg/dl in women) have been associated with an increased risk of coronary heart disease (CHD) (1). Marked HDL deficiency states (HDL cholesterol , 5 mg/dl) and undetectable plasma apolipoprotein A-I (apoA-I) levels have been reported in humans as a result of mutations at the APOA1/C3/A4 gene locus (2-18). Such patients lack apoA-I-containing HDL in plasma, with normal or decreased triglyceride levels, normal LDL cholesterol levels, and often strikingly premature CHD (2-18). Other patients with marked HDL deficiency have mutations affecting the apoA-I sequence that can affect the activity of lecithin:cholesterol acyl transferase activity (19)(20)(21)(22)(23)(24)(25)(26). In this regard, they differ from patients with homozygous Tangier disease caused by mutations in ABCA1, who have defective cellular cholesterol efflux, detectable plasma apoA-I in preb-1 HDL only, hypertriglyceridemia, and decreased LDL cholesterol (27-29). Previously, defects involving the APOA1/C3/A4 gene cluster, the contiguous APOA1 and APOC3 genes, and the APOA1 gene in isolation have been described (2-26). Here, we report a kindred with isolated apoA-I deficiency, with precise lipoprotein and clinical characterization and characterization of fat-soluble vitamin levels, and document differences between this type of apoA-I deficiency and those combined with other apolipoprotein deficiencies in humans. These data provide us with important insights about the function of these apolipoproteins in human health and disease as well as about HDL particle subspecies. METHODS KindredThe index case presented to the Lipid Clinic at the Heart Institute (InCor) of the Uni...

In individuals with hFH, severe periodontitis was associated with a higher DBP, which suggests that severe periodontitis, itself, may contribute to the increased cardiovascular risk profile in this population.

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Abstract-Nonsteroidal anti-inflammatory drugs and calcium channel blockers can reduce inflammatory responses.Leukocytes play an important role in these responses. An increased expression of adhesion molecules may increase leukocyte migration. Verapamil and diclofenac are known to reduce leukocyte-endothelium interaction. To investigate a possible synergism between these drugs that could be beneficial in cardiovascular diseases, we studied leukocyte behavior by using intravital microscopy. Venules of the spermatic fascia of anesthetized Wistar rats were observed with a closed-circuit TV coupled to an optical microscope. The number of leukocytes rolling along the venular endothelium ("rollers"), sticking after application of a stimulus such as leukotriene B 4 or zymozan-activated plasma ("stickers"), or migrating after a carrageenan stimulus was reduced by verapamil at the dose of 10 mg/kg IP and by diclofenac at the dose of 2.5 mg/kg IP. The combination of both did not augment the effect of each agent alone. Verapamil, diclofenac, or their combination did not interfere with vessel diameter, number of circulating leukocytes, blood pressure levels, or heart rate. Verapamil alone or together with diclofenac reduced venular blood flow velocity and in consequence, the venular shear rate. Our data allow us to suggest that these drugs might interfere with the expression of adhesion cell molecules to reduce cell migration in inflammation. The lack of synergism between the drugs might be explained by the reduction in venular shear rate induced by verapamil, which might not be sufficient to hinder the effect of verapamil alone but hindered the summation effects of both. Key Words: anti-inflammatory agents, nonsteroidal Ⅲ verapamil Ⅲ cell adhesion molecules Ⅲ endothelium Ⅲ cell movement Ⅲ leukocytes Ⅲ microcirculation L eukocyte extravasation is essential in the inflammatory response and can be divided into 3 steps: initial interaction of leukocytes with the activated endothelium (rolling), leukocyte activation with firm adhesion to endothelial cells (sticking), and leukocyte extravasation into the surrounding tissues. 1,2 Several adhesion molecules are involved in the interaction between leukocytes and vascular endothelial cells, which include E-selectin, vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1). 3 An increased expression of adhesion molecules may increase leukocyte migration and contribute to end-organ damage in cardiovascular diseases. 3 Calcium channel blockers 4 and nonsteroidal anti-inflammatory drugs 5 are known to reduce the expression of several adhesion molecules and reduce leukocyte-endothelium interaction.Diclofenac, a nonsteroidal anti-inflammatory drug, reduces inflammation, swelling, and arthritic pain by inhibiting the production of prostaglandins. 6 -8 Diclofenac affects polymorphonuclear leukocyte function in vitro, reducing chemotaxis, superoxide radical generation, and neutral protease production. 9 Diclofenac also reduces the expression of several adhesi...

Many patients with hypertension, particularly elderly patients, take nonsteroidal antiinflammatory drugs (NSAIDs) and antihypertensive agents. However, few studies describe the effect of the association of antihypertensive agents with NSAIDs on inflammatory response in hypertension. To investigate this, spontaneously hypertensive rats (SHRs) were treated with either diclofenac alone or diclofenac combined with losartan (an AT1 angiotensin II antagonist). The leukocyte-endothelial interaction was then observed using intravital microscopy. Blood pressure of SHR (169.6+/-3.6) was increased by diclofenac (186.4+/-2.9), reduced by losartan (152.6+/-3.5), and reduced by the combination of the 2 (158.9+/-3.7). All the treatments tested reduced the number of rollers, adherent and migrated leukocytes, and the expression of endothelial intercellular adhesion molecule-1 and P-selectin. The association of losartan reduced the effect of diclofenac on leukocyte migration. Neither treatment tested increased the venular shear rate or modified the venular diameters, number of circulating leukocytes, and L-selectin expression on granulocytes. The reduction of CD11/CD18 expression induced by diclofenac alone was hindered by losartan. A pharmacokinetic interference between losartan and diclofenac was ruled out since no significant differences were observed in the plasma concentrations of each drug when they were associated. In conclusion, although diclofenac does not interfere with the losartan antihypertensive effect, losartan attenuates the effect of diclofenac has on leukocyte behavior and expression of adhesion molecules. Losartan has an antimigratory effect, reducing leukocyte migration by reducing ICAM-1 and P-selectin expression. Losartan may hinder the full expression of the antimigratory effect of diclofenac.