Hypercholesterolemia Hypercholesterolemic

A comprehensive, randomized, placebo-controlled trial of infused bolus L-arg and its enantiomer (D-arg) included healthy subjects, non-insulin dependent diabetics, hypertensive subjects, and normotensives with primary hypercholesterolemia [147]. A blood-pressure drop and an acute inhibition of ADP-induced aggregation in platelet-rich plasma were observed in all subjects after L-arg administration (<5 g). Both responses to L-arg infusion closely correlated in magnitude, were weaker in noninsulin dependent diabetics and hypercholesterolemics, and declined with increasing age. Notably, D-arg did not elicit any of the L-arg effects, which were reduced by some 70% when superimposed upon ongoing, nonselective NOS inhibition with infused L-N-monomethyl-arginine (L-NMMA). Since D-arg is not a NOS substrate, and L-NMMA is a substrate-competitive NOS inhibitor, the L-arg effects observed in this study were theorized to reflect a rise in vascular NO production by eNOS. In contrast, the inhibition of platelet aggregation observed in vitro after a 5 min L-arg infusion (160 mg total dose) into healthy subjects and patients with angiographic... 

Hypercholesterolemia is well established as a risk factor for atherosclerosis. Dietary flavonoids are thought to protect against the disease by exerting hypocholesterolemic effects. However, clinical studies are not conclusive enough to provide the supporting evidence. Recent clinical studies on both normo- and hypercholesterolemic subjects with different flavonoids sources lasting 1-13... 

The hypocholesterolemic eflFect of L-ascorbic acid is most prevalent in humans with low levels of tissue ascorbate and in whom hypercholesterolemia results from a chronic imbalance between an enhanced input of exogenous or endogenous cholesterol and a reduced output in the form of bile acids. The most striking hypocholesterolemic eflFect of ascorbate has been observed in elderly hypercholesterolemic humans... 

Fig. 7. Endothelium-dependent vasodilation is inversely related to autoantibodies against plasma oxidized low density lipoprotein (LDL) [data from Heitzer etal. (70), reproduced with permission]. Vascular response to the endothelium-dependent agent acetylcholine was studied in normal control subjects (n = 10), patients with hypercholesterolemia (n = 15), long-term smokers (n = 15), and hypercholesterolemic patients who smoked (n = 15). Acetylcholine was infused into the brachial artery, and forearm blood flow (FBF) was measured by venous occlusion plethysmography. FBF responses to acetylcholine were significantly blunted in all three patient groups compared with normal control subjects (P< 0.05) and were associated with higher autoantibody titers to oxidized LDL.

An isolated defect in bile acid production has been found so far only in familial hypercholesterolemia (62), though even in this entity cholesterol catabolism as a whole may be decreased. Essential hypercholesterolemics (11) and hypothyroid patients (11,89) also tend to have a low bile salt elimination, though the excretion of cholesterol as such appears to decrease, too, particularly in the latter condition. In the circumstances in which bile salt elimination is decreased as a result of decreased hepatic function, elimination of cholesterol as such is also reduced (11). Under these conditions, serum cholesterol apparently increases only when the amount of elimination is decreased more than the feedback mechanism(s) are able to suppress synthesis, i.e., when the production exceeds elimination. 

Hyperlipidemia is known to be one of the most potent factor associated with the premature development of atheromatous arterial disease. Thus an increased serum cholesterol level is frequently found in patients with ischemic heart disease and myocardial infarction, and hypercholesterolemic patients have a high incidence of coronary artery disease. Therefore, because cholesterol is partially eliminated from the body as bile acids (see Section VB), it would be important to know the role of bile acid metabolism in the development of different types of hypercholesterolemia. 

Another group of hypercholesterolemic (type II) patients, indicated in Table II by the term essential hypercholesterolemia, was also studied. These patients differed from familial hypercholesterolemia patients in that the family history was less clear, serum cholesterol was less elevated, and xanthomata were not present. Hypercholesterolemia may be primarily caused by environmental, primarily dietary, factors. Bile acid production in this group is less significantly reduced than in the familial group, and the relative catabolism of cholesterol by way of bile acids is within normal limits. Sodhi (151) observed in this type of hypercholesterolemia a markedly low fecal bile acid excretion. 

In agreement with the findings presented above, the turnover of cholic acid has been reported to be low in patients with hypercholesterolemia (73, 152). Production of cholic and chenodeoxycholic acids has also been shown to be markedly lower in hypercholesterolemic than in triglyceridemic patients, the former subjects exhibiting a smaller cholic but not chenodeoxycholic acid pool than the latter ones (69). 

The reason for the low bile acid formation in familial hypercholesterolemia is not known. It could be due to impaired availability of cholesterol to the pool which is utilized for bile acid synthesis, a partial deficiency or inhibition of the enzyme system producing bile acids, deficient hepatic secretion of bile acids, or augmented intestinal reabsorption. An interesting observation is that the bile of hypercholesterolemic patients may contain relatively little or no deoxycholic acid (23,73,157), a finding recorded also in patients... 

Ileal bypass (see Section VB2) performed for hypercholesterolemic patients (269) increased cholesterol elimination in the study by Moore et al. (156) about fivefold as bile acids and threefold as neutral steroids according to the isotopic balance technique. Serum cholesterol reduction was about 40 %. In our own series, consisting of patients with familial hypercholesterolemia only, similar results have been obtained by the chemical balance technique except that elimination of cholesterol increased solely as bile acids (11,63,127). The fecal bile salt loss was associated with a 35 % fall in the serum cholesterol level, a severalfold increased cholesterol synthesis, impaired micellar solubilization of digested lipids, reduced intestinal bile salt concentrations, and decreased cholesterol level in the intestinal contents. The last suggests that biliary secretion of cholesterol was markedly decreased so that, despite impaired cholesterol reabsorption, fecal neutral steroid excretion remained quite unchanged. An increased fecal bile salt loss associated with stimulated cholesterol production has been reported also by Grundy et al. (94). 

We also studied LpB immunoheterogeneity in 24 subjects with familial hypercholesterolemia and observed that particles recognized by monoclonal antibodies and particularly by BL3 are relatively more abundant in hypercholesterolemic patients than in controls. 

Triton is a detergent and like cholic acid, which is an endogenous detergent, it causes hypercholesterolemia in the rat when injected intravenously. The water-soluble triton WR-1339, as supplied by the Roehm and Hass Company, is a polymeric -isooctyl-polyoxy-ethylenephenol. The hyperlipemic and hypercholesterolemic effect of triton was first observed in the rabbit by Kellner et al. [242]. The triton-effect in the rat has been further elaborated by Friedman and Byers [243]. 

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