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PubMedDate not supplied

High "population attributable fraction" for coronary heart disease mortality among relatives in monogenic familial hypercholesterolemia.

PURPOSE: To estimate "population attributable fraction" (PAF) for coronary heart disease (CHD) mortality in a population of first-degree relatives of patients with monogenic familial hypercholesterolemia (FH) compared with the PAF for hypercholesterolemia in the general population. METHODS: PAF was calculated as [f(R - 1)/[1 + f(R - 1)]], where f is the frequency of the risk factor (hypercholesterolemia) and R is the relative risk for the association of hypercholesterolemia and CHD death. For FH relatives, f was assumed to be 50%, based on a fully penetrant, dominant mode of inheritance, and R values were obtained from the prospective Simon Broome Register data. PAFs for hypercholesterolemia and CHD death in the general population were based on the Framingham risk equations for the 95th percentile of cholesterol and CHD mortality. RESULTS: Over all ages, 44% and 57% of 5-year CHD mortality could potentially be prevented among male and female first-degree relatives in FH families, respectively, by cholesterol reduction. In contrast, values for 5-year CHD death for hypercholesterolemia in the general population were uniformly lower at all ages, with overall 5% and 10% of fatal CHD prevented among men and women, respectively. CONCLUSION: These results strongly support the view that family based testing strategies of relatives of probands with monogenic hypercholesterolemia, followed by effective lipid lowering drug treatment, is a highly effective way of reducing CHD deaths among these relatives.

Adult↗

PubMed1991

Family studies of the LDL receptor gene of relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas.

To assess the relationship between relatively severe hereditary hypercholesterolemia with Achilles tendon xanthomas and the defect of the low density lipoprotein (LDL) receptor gene, family studies were carried out in 17 hypercholesterolemic families. In 16 out of the 17 families, hypercholesterolemia co-segregated with four different gross rearrangements, six different restriction fragment length polymorphism (RFLP) haplotypes, or an abnormal TaqI band of the LDL receptor gene. These findings are compatible with the interpretation that hypercholesterolemia is caused by defective LDL receptor genes, and that the origin of the mutant LDL receptor genes in Japanese generally differs among different pedigrees. In the remaining family, the proband and his sibling, both having relatively severe hypercholesterolemia and Achilles tendon xanthomas, shared an RFLP haplotype, although the proband's other sibling with moderate hypercholesterolemia but without Achilles tendon xanthomas did not. The mutant gene for familial defective apolipoprotein B-100 was not detected in the 17 probands. These data suggest that most, if not all, of the relatively severe hereditary hypercholesterolemia associated with Achilles tendon xanthomas is caused by a defect of the LDL receptor gene.

Achilles Tendon↗

PubMed2004

Effect of hypercholesterolemia on inducible nitric oxide synthase expression in a rat model of elevated intraocular pressure.

PURPOSE: This study was performed to examine the effect of hypercholesterolemia on inducible nitric oxide synthase (NOS-2) expression and oxidative tissue injury in an experimental rat model of elevated IOP. METHODS: Wistar rats were maintained on either regular chow or a high-cholesterol diet for 24 weeks. Intraocular pressure (IOP) was elevated in hypercholesterolemic rats by unilaterally cauterizing three episcleral vessels. Rats were divided into four experimental groups as follows; hypercholesterolemia, hypercholesterolemia+elevated IOP, elevated IOP and control. NOS-2 distribution, lipid peroxidation and retinal nerve fiber layer (RNFL) thickness was evaluated in all experimental groups at the end of 24 weeks. RESULTS: Light microscopic evaluation of retinas in hypercholesterolemic rats revealed breaks and discontinuation in focal areas in the outer nuclear layer (ONL). NOS-2 positive staining was observed throughout the outer plexiform layer (OPL), inner plexiform layer (IPL) and ganglion cell layer (GCL) in rats with elevated IOP and/or hypercholesterolemia. Calculated values of RNFL thickness in hypercholesterolemic rats were significantly higher than those in the control and elevated IOP group. Vitreous malondialdehyde (MDA) levels detected in elevated IOP (3.51+/-0.31 nmol/mg protein) and hypercholesterolemia+elevated IOP (5.14+/-1.28 nmol/mg protein) groups were significantly higher than those detected in hypercholesterolemic (1.92+/-1.43 nmol/mg protein) and control (1.89+/-0.24 nmol/mg protein) groups. CONCLUSION: The presented data confirms hypercholesterolemia as a risk factor in the development of glaucomatous optic neuropathy (GON) and suggests that increased circulating cholesterol may exacerbate disease progression by inducing NOS-2 expression and elevating oxidant tissue injury.

Animals↗

PubMed1999

Metabolic vasodilation in the human forearm is preserved in hypercholesterolemia despite impairment of endothelium-dependent and independent vasodilation.

OBJECTIVE: Hypercholesterolemia has been shown to impair endothelium-mediated, nitric oxide (NO)-dependent responses to acetylcholine (ACh), serotonin, substance P and flow-mediated dilation. We have recently shown that NO contributes to metabolic vasodilation in the human forearm. We sought to determine whether metabolic vasodilation is impaired in healthy subjects with hypercholesterolemia. METHODS: We compared the forearm blood flow (FBF) responses to isotonic exercise, ACh and the endothelium-independent vasodilator sodium nitroprusside in young, otherwise healthy volunteers with hypercholesterolemia and controls before and after the NO inhibitor NG-monomethyl-L-arginine (L-NMMA). FBF was measured using venous occlusion plethysmography. Hypercholesterolemic (n = 20) and control (n = 20) subjects were age- and gender-matched. RESULTS: Total cholesterol (6.9 +/- 0.3 vs. 4.6 +/- 0.1 mmol/l, P < 0.0001), low density lipoprotein (4.9 +/- 0.4 vs. 2.7 +/- 0.1 mmol/l, P < 0.001) and triglyceride (1.3 +/- 0.2 vs. 0.8 +/- 0.1 mmol/l, P = 0.005) levels were higher in the hypercholesterolemic group. Basal FBF and resistance were similar in the two groups. Hypercholesterolemia impaired the peak FBF response to ACh (11.1 +/- 1.9 vs. 17.6 +/- 2.2 ml/100 ml/min, P = 0.03), and reduced the peak response to sodium nitroprusside (6.0 +/- 0.4 vs. 8.1 +/- 0.6 ml/100 ml/min, P < 0.01). However, hypercholesterolemia did not affect peak hyperemic FBF (13.1 +/- 1.0 vs. 13.2 +/- 1.0 ml/100 ml/min, P = 1.0) or the FBF volume repayment during the 1 or 5 min after exercise. Resting FBF was reduced by L-NMMA to a similar degree (by 33% vs. 40%, P = 0.17) in both groups. Although L-NMMA reduced peak hyperemic FBF (by 16% vs. 17%, P = 0.93) and the volume repaid after exercise in both groups, there were no differences between the two groups. CONCLUSIONS: Exercise-induced metabolic vasodilation is in part dependent on NO release. Hypercholesterolemia impairs NO-mediated vasodilation, but is not associated with a reduction in exercise-induced hyperemia. This may indicate that multiple compensatory mechanisms are operative in skeletal muscle metabolic vasodilation.

Acetylcholine↗

PubMed2001

Effect of simvastatin on monocyte adhesion molecule expression in patients with hypercholesterolemia.

Increased monocyte adherence to the vessel wall is one of the earliest events in atherosclerosis. The mechanism by which hypercholesterolemia causes alterations in endothelial adhesiveness for monocytes is unclear. This study sought to determine if monocyte adhesion molecule expression is affected by low-density lipoprotein (LDL)-cholesterol levels. Patients with hypercholesterolemia and stable coronary artery disease were compared with those without major cardiovascular risk (control). Patients with hypercholesterolemia were treated with simvastatin 20--40 mg/day for 8--10 weeks. Blood samples were examined with flow cytometry assays at baseline and after cholesterol-lowering therapy. Monocyte CD11b and CD14 adhesion molecule expression, measured as fluorescence intensity, were significantly (P<0.0001) higher in hypercholesterolemic patients before the study (176.9+/-9.8 and 138.0+/-4.8, respectively) when compared with that in control subjects (97.2+/-8.1 and 84.0+/-6.4, respectively). Both decreased markedly with treatment: to 118.8+/-6.9 and 103.1+/-3.9, respectively. Monocyte L-selectin expression was significantly lower in patients with hypercholesterolemia before treatment (43.0+/-3.0) when compared with control subjects (79.9+/-2.7), and it increased markedly with treatment (54.2+/-2.5). LDL levels correlated directly with both CD11b and CD14 expression and correlated inversely with L-selectin expression. These data show that hypercholesterolemia affects monocyte adhesion molecule expression which, in turn, decreases with statin-induced plasmatic cholesterol reduction. Such perturbations in monocyte function likely represent a proinflammatory response to hypercholesterolemia and may have a role in the early progression of atherogenesis.

Adult↗

PubMed2002

Increased central pulse pressure and augmentation index in subjects with hypercholesterolemia.

OBJECTIVES: The goal of this study was to investigate the relation between serum cholesterol, arterial stiffness and central blood pressure. BACKGROUND: Arterial stiffness and pulse pressure are important determinants of cardiovascular risk. However, the effect of hypercholesterolemia on arterial stiffness is controversial, and central pulse pressure has not been previously investigated. METHODS: Pressure waveforms were recorded from the radial artery in 68 subjects with hypercholesterolemia and 68 controls, and corresponding central waveforms were generated using pulse wave analysis. Central pressure, augmentation index (AIx) (a measure of systemic stiffness) and aortic pulse wave velocity were determined. RESULTS: There was no significant difference in peripheral blood pressure between the two groups, but central pulse pressure was significantly higher in the group with hypercholesterolemia (37 +/- 11 mm Hg vs. 33 +/- 10 mm Hg [means +/- SD]; p = 0.028). Augmentation index was also significantly higher in the patients with hypercholesterolemia group (24.8 +/- 11.3% vs. 15.6 +/- 12.1%; p < 0.001), as was the estimated aortic pulse wave velocity. In a multiple regression model, age, short stature, peripheral mean arterial pressure, smoking and low-density lipoprotein cholesterol correlated positively with AIx, and there was an inverse correlation with heart rate and male gender. CONCLUSIONS: Patients with hypercholesterolemia have a higher central pulse pressure and stiffer blood vessels than matched controls, despite similar peripheral blood pressures. These hemodynamic changes may contribute to the increased risk of cardiovascular disease associated with hypercholesterolemia, and assessment may improve risk stratification.

Adult↗

PubMed2002

K(ATP) channel opening is an endogenous mechanism of protection against the no-reflow phenomenon but its function is compromised by hypercholesterolemia.

OBJECTIVE: This study aimed to clarify the role of adenosine triphosphate-sensitive K(+) (K(ATP)) channels in the no-reflow phenomenon and in its extension by hypercholesterolemia. BACKGROUND: The no-reflow phenomenon is an important target of therapy in patients with acute myocardial infarction, but its mechanism remains unclear. METHODS: The left circumflex coronary artery was occluded for 30 or 60 min and reperfused in rabbit hearts in situ. The no-reflow zone, area at risk, and infarct size were determined by thioflavin-S, Evans blue, and tetrazolium staining, respectively. No-reflow zone size was expressed as a percentage of infarct size (%NR/IS). Hypercholesterolemia was induced by two weeks of cholesterol-enriched diet. RESULTS: A K(ATP) channel blocker, glibenclamide (0.3 mg/kg), increased %NR/IS after 30-min ischemia/90-min reperfusion from 33.6 +/- 1.9% to 45.9 +/- 1.6% and %NR/IS after 60-min ischemia/90-min reperfusion from 32.8 +/- 3.4% to 46.1 +/- 1.7%. However, N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide (NO) synthase inhibitor, and nicorandil, a hybrid of K(ATP) channel opener and nitrate, failed to significantly modify %NR/IS. Hypercholesterolemia increased %NR/IS to 61.6 +/- 0.6%, which was not further enlarged by glibenclamide, and delayed infarct healing during the subsequent five days of reperfusion. These effects of hypercholesterolemia were significantly suppressed by nicorandil. Neither glibenclamide, L-NMMA, nicorandil, nor hypercholesterolemia modified infarct size. CONCLUSIONS: The K(ATP) channel activation, but not NO, is a major mechanism of protection against microvascular injury, causing the no-reflow phenomenon in the heart. Suppression of K(ATP) channel opening may underlie the hypercholesterolemia-induced extension of no-reflow, which delays infarct healing.

Adenosine Triphosphate↗

PubMed2002

Hypercholesterolemia in minipigs impairs left ventricular response to stress: association with decreased coronary flow reserve and reduced capillary density.

BACKGROUND: Hypercholesterolemia induces functional and structural changes of the microvasculature and reduces coronary flow reserve in humans and experimental animals. The effect of hypercholesterolemia on left ventricular (LV) function in the absence of coronary stenosis is, however, unknown. Our objective was therefore to assess the effect of hypercholesterolemia and cholesterol withdrawal on LV function in the presence of advanced coronary plaques that do not cause stenosis. METHODS AND RESULTS: Twenty-eight minipigs on cholesterol diet for 34 weeks and 16 control pigs were studied. Seven hypercholesterolemic pigs were withdrawn from the diet for 26 weeks. LV function was assessed with cine-MRI, myocardial blood flow with colored microspheres, and capillary density with immunohistochemistry, and microvascular endothelial cell apoptosis with terminal dUTP nick-end labeling staining. Hypercholesterolemia (17+/-8 versus 268+/-150 versus 12+/-10 mg/dL LDL cholesterol, control versus hypercholesterolemic versus cholesterol withdrawal; P<0.001) induced atherosclerosis but not stenosis in the left coronary artery. Baseline cardiac output, ejection fraction, and stroke volume were similar in control and hypercholesterolemic pigs. In dobutamine stress test, cardiac output (P<0.05) and stroke volume (P<0.01) were lower in hypercholesterolemic pigs compared with controls. The impaired response to dobutamine was reversible by dietary cholesterol withdrawal. Hypercholesterolemia reduced endomyocardial coronary flow reserve (P<0.01) and capillary density (P<0.05) and induced capillary endothelial cell apoptosis. Hypercholesterolemic pigs failed to reduce vascular resistance in response to increased LV workload and pharmacological vasodilation. CONCLUSION: LDL hypercholesterolemia in minipigs impaired LV response to dobutamine stress in the absence of coronary stenosis.

Adrenergic beta-Agonists↗

PubMed2004

Hypercholesterolemia stimulates angiotensin peptide synthesis and contributes to atherosclerosis through the AT1A receptor.

BACKGROUND: Hypercholesterolemia-induced atherosclerosis is attenuated by either pharmacological antagonism of AT1 receptors or AT1A receptor deficiency. However, the mechanism underlying the pronounced responses to angiotensin II (Ang II) antagonism has not been determined. We hypothesized that hypercholesterolemia stimulates the production of angiotensin peptides to provide a rationale for the profound effect of AT1A receptor deficiency on atherogenesis. METHODS AND RESULTS: Atherosclerotic lesions were analyzed in LDL receptor-deficient mice. Immunocytochemical analysis demonstrated that atherosclerotic lesions contained all the components of the conventional pathway for Ang II synthesis. AT1A receptor deficiency caused a marked decrease in atherosclerotic lesion size in both the aortic root and arch of male and female mice, without a discernible effect on composition. AT1A receptor deficiency-induced reductions in atherosclerosis were independent of systolic blood pressure and measurements of oxidation and chemoattractants. Aortic AT2 receptor mRNA expression was not altered in AT1A receptor-deficient mice, and AT2 receptor deficiency had no effect on lesion area or cellular composition. Hypercholesterolemia greatly augmented the systemic renin-angiotensin system, as demonstrated by large increases in plasma concentrations of angiotensinogen and angiotensin peptides (Ang II, III, IV, and 4-8). These increases were ablated in hypercholesterolemic AT1A receptor-deficient mice. CONCLUSIONS: AT1A receptor deficiency had a striking effect in reducing hypercholesterolemia-induced atherosclerosis in LDL receptor-negative mice. Hypercholesterolemia was associated with increased systemic angiotensinogen and angiotensin peptides, which were reduced in AT1A receptor-deficient mice. These results demonstrate that hypercholesterolemia-induced stimulation of angiotensin peptide production provides a basis for the marked effect of AT1A receptor deficiency in reducing atherosclerosis.

Amino Acid Sequence↗

PubMed1991

Hypercholesterolemia enhances macrophage recruitment and dysfunction of regenerated endothelium after balloon injury of the rabbit iliac artery.

BACKGROUND: We studied the effects on and possible interaction of balloon denudation and hypercholesterolemia on large arteries in the rabbit with special regard to structure and vascular reactivity. METHODS AND RESULTS: New Zealand White rabbits fed a 1% cholesterol diet or a standard diet for 14 weeks underwent balloon denudation of the left iliac artery 4 weeks before death. Both the balloon-injured and the control iliac arteries were harvested for in vitro studies of vascular reactivity, for immunohistochemical staining with monoclonal antibodies directed at smooth muscle cells and macrophages, and for scanning electron microscopy. Balloon injury caused intimal smooth muscle proliferation with little macrophage infiltration and was followed by recovery of endothelium-dependent vasodilator function within 4 weeks. Hypercholesterolemia caused macrophage-rich lesions confined to the intima with moderate impairment of endothelial vasodilator function. Balloon injury in the setting of hypercholesterolemia caused intimal smooth muscle cell proliferation and intense macrophage infiltration throughout the arterial wall and severe impairment of endothelial vasodilator function. Scanning electron microscopy confirmed regrowth of the endothelium in all balloon-injured vessels. In the balloon-injured arteries of hypercholesterolemic animals, the regenerated endothelium exhibited areas of atypical morphology not seen after balloon injury or hypercholesterolemia alone. CONCLUSIONS: The present study shows that balloon injury, hypercholesterolemia, and their combination cause distinct lesions and functional disturbances. An arterial balloon injury in the setting of hypercholesterolemia produces a diffuse inflammatory response that is accompanied by a sustained impairment of endothelial function and a marked proliferative response.

Animals↗

PubMed2001

Combination of hypercholesterolemia and hypertension augments renal function abnormalities.

Hypercholesterolemia and hypertension are both risk factors for end-stage renal disease. This study was designed to examine whether their coexistence augmented impairment in renal function and redox status. Regional renal hemodynamics and function in response to vasoactive challenges with acetylcholine or sodium nitroprusside were quantified by using electron-beam computed tomography in pigs after 12 weeks of either a normal (n=10) or hypercholesterolemic (n=10) diet, renovascular hypertension (n=7), or combined hypercholesterolemia+hypertension (n=6). The hypercholesterolemic and hypercholesterolemic+hypertensive groups had significantly increased serum cholesterol levels, whereas in the hypertensive and hypercholesterolemic+hypertensive groups, mean arterial pressure was significantly elevated compared with the group fed a normal diet. Basal regional renal perfusion and glomerular filtration rates were similar among the groups. In response to acetylcholine, cortical perfusion increased in normal animals (15.6+/-4.7%, P=0.002) but not in hypercholesterolemic or hypertensive animals (8.0+/-7.4% and 8.2+/-5.9%, respectively; P>0.05). Moreover, in the hypercholesterolemic+hypertensive group, cortical perfusion response was further attenuated (2.5+/-4.8%, P=0.02) and significantly different from the group fed a normal diet (P<0.05). The response to sodium nitroprusside followed a similar pattern, and the impairment was augmented in the hypercholesterolemic+hypertensive group. The functional abnormalities in hypercholesterolemia or hypertension were associated with a decrease in systemic and/or renal tissue levels of oxygen radical scavengers that was again accentuated in hypercholesterolemia+hypertension. These results demonstrate that concurrent hypercholesterolemia and hypertension have a greater detrimental effect on renal perfusion responses compared with hypercholesterolemia or hypertension alone, associated with a marked pro-oxidant shift in redox status. These effects may potentially augment renal functional impairment and play a role in the initiation and progression of renal injury in hypertension and atherosclerosis.

Acetylcholine↗

PubMed1988

Loss of selective endothelial cell vasoactive functions caused by hypercholesterolemia in pig coronary arteries.

The influence of hypercholesterolemia on the reactivity of coronary arteries was investigated after feeding a high-cholesterol diet to pigs for 9 weeks. After this duration of hypercholesterolemia, the fatty or intimal proliferative changes of atherosclerosis were not yet evident in the coronary arteries by light or electron microscopy. Changes in isometric tension were compared in isolated ring segments of coronary arteries from normal and hypercholesterolemic animals. The endothelium failed to inhibit contractions caused by 5-hydroxytryptamine in coronary arteries from hypercholesterolemic animals, but it did so in normal vessels. In contracted arteries, endothelium-dependent relaxations caused by 5-hydroxytryptamine and substance P were reduced by hypercholesterolemia. In contrast, endothelium-dependent relaxations mediated by norepinephrine acting at alpha 2-adrenoceptors and those caused by the calcium ionophore A23187 were unaffected. Endothelium-independent beta-adrenergic relaxations caused by norepinephrine, as well as those caused by nitroprusside, and papaverine also were unaffected by hypercholesterolemia. The loss of selective endothelial cell receptor-mediated relaxation suggests that it is not the ability of the coronary artery endothelium to elaborate vasodilators, but the initiation of the coronary artery endothelial cell response to 5-hydroxytryptamine and substance P that is affected by hypercholesterolemia. Thus, during hypercholesterolemia, selective endothelial cell dysfunction giving rise to abnormal coronary artery reactivity precedes the onset of coronary artery atherosclerosis.

Animals↗

PubMed2001

Upregulation of CD40 and CD40 ligand (CD154) in patients with moderate hypercholesterolemia.

BACKGROUND: Hypercholesterolemia, a risk factor for cardiovascular disease, is associated with inflammation and hypercoagulability. Both can be mediated by the CD40 system. This study investigated whether the CD40 system is upregulated in patients with moderate hypercholesterolemia and whether it is influenced by therapy with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor. METHODS AND RESULTS: Fifteen patients with moderate hypercholesterolemia and 15 healthy control subjects were investigated. CD154 and P-selectin were analyzed on platelets and CD40 was analyzed on monocytes before and under therapy with the statin cerivastatin by double-label flow cytometry. Blood concentrations of soluble CD154 and monocyte chemoattractant protein-1 (MCP-1) were evaluated. Our main findings were as follows. Patients with moderate hypercholesterolemia showed a significant increase of CD154 and P-selectin on platelets and CD40 on monocytes compared with healthy subjects. Soluble CD154 showed a nonsignificant trend for higher plasma levels in patients. A positive correlation was found for total or LDL cholesterol and CD154, but not for CD40 on monocytes. The latter was upregulated in vitro by C-reactive protein, which was found to be significantly elevated in patients with moderate hypercholesterolemia. CD154 on platelets proved to be biologically active because it enhanced the release of MCP-1, which was markedly elevated in an in vitro platelet-endothelial cell coculture model and in the serum of patients. Short-term therapy with a HMG-CoA reductase inhibitor significantly downregulated CD40 on monocytes and serum levels of MCP-1. CONCLUSION: Patients with moderate hypercholesterolemia show upregulation of the CD40 system, which may contribute to the known proinflammatory, proatherogenic, and prothrombotic milieu found in these patients.

Adult↗

PubMed1978

Genetics of the low density lipoprotein receptor. Diminished receptor activity in lymphocytes from heterozygotes with familial hypercholesterolemia.

Using circulating mononuclear cells as a readily available tissue and using the rate of high affinity degradation of 125-I-labeled low density lipoprotein (LDL) as an index of cell surface LDL receptor activity, we have measured receptor activity in cells from 53 individuals. This group includes 32 healthy subjects, 15 subjects with the heterozygous form of familial hypercholesterolemia, and 6 subjects with hyperlipidemic disorders other than familial hypercholesterolemia. 7 of the healthy subjects and 10 of the heterozygotes were members of a single large kindred with five-generation transmission of the mutant familial hypercholesterolemia gene. LDL receptor activity was assayed in blood mononuclear cells under two sets of conditions. First, 125I-LDL degradation was measured in purified lymphocytes that had been incubated for 3 days in the absence of lipoproteins so as to induce a high level of LDL receptor activity. Phase-contrast autoradiograms of cells incubated with 125I-LDL and electron micrographs of cells incubated with ferritin-labeled LDL confirmed the existence of LDL receptors on lymphocytes. Second, 125I-LDL degradation was measured in mixed mononuclear cells (85-90% lymphocytes and 5-15% monocytes) immediately after their isolation from the bloodstream. This assay represented an attempt to assess the number of receptors actually expressed on the cells when they were in the circulation. Under both sets of conditions, cells from the familial hypercholesterolemia heterozygotes expressed an average of about one-half the normal number of LDL receptors. The current findings are consistent with the conclusion that heterozygotes with familial hypercholesterolemia possess only one functional allele at the LDL receptor locus and that the consequent deficiency of LDL receptors produces the clinical syndrome of heterozygous familial hypercholesterolemia.

Adhesiveness↗

PubMed2005

High diastolic blood pressure during exercise is associated with hypercholesterolemia in patients with coronary artery disease.

Evaluating blood pressure response during exercise rather than during rest might better detect a subtle impairment in relaxation of the resistance vessel in hypercholesterolemia. We examined the relation between serum cholesterol and blood pressure response during exercise in patients with coronary artery disease. One hundred and forty-eight consecutive patients with coronary artery disease were monitored during symptom-limited incremental exercise testing with a cycle ergometer. Cuff blood pressure was measured every minute during exercise testing with an automatic indirect manometer. Although there were no significant differences in systolic or diastolic blood pressure at rest between the patients with hypercholesterolemia (total cholesterol > or = 220 mg/dL, n = 39) and those without it (n = 109), the former reached a higher diastolic blood pressure at peak exercise (94.8+/-16.0 versus 87.8+/-12.9 mmHg, P = 0.007). The increase in diastolic blood pressure at peak exercise versus the resting value in the patients with hypercholesterolemia was 20.6+/-11.3 mmHg, and this was significantly higher than the increase in patients without hypercholesterolemia (14.8+/-11.8 mmHg, P = 0.009). However, there were no differences in the peak exercise systolic blood pressure and the magnitude of the increase in systolic blood pressure between the two groups. Among the patients with coronary artery disease in our study, we found that those with hypercholesterolemia had significantly higher diastolic blood pressure during exercise than those without hypercholesterolemia, strongly suggesting that patients with hyperlipidemia are at a higher risk of developing hypertensive complications.

Aged↗

PubMed2003

Platelet activation, inflammatory mediators and hypercholesterolemia.

Atherogenic cofactors, such as altered cholesterol metabolism, may impact locally on inflammatory responses in atherosclerotic lesions. Blood levels of inflammatory markers (e.g., C-reactive protein, fibrinogen) have been associated with hypercholesterolemia and with overt atherothrombotic disorders. More recently. cytokines (e.g., interleukin-6, interleukin-1beta) and soluble adhesion molecules (e.g., selectins, intercellular adhesion molecule-1, vascular cell adhesion molecule-1) have been associated with both hypercholesterolemia and atherosclerotic disease, suggesting their use as potential therapeutic targets for the non-specific "anti-inflammatory" treatment of atherosclerosis. The inflammatory response associated with hypercholesterolemia involves not only the intrinsic cells of the artery wall. but also circulating cells. Platelets participate in this disease process through the release of a wide variety of biologically active substances. An imbalance of the hemostatic system and persistent in vivo platelet activation can be observed in hypercholesterolemia and may have pathophysiological implications in the development and progression of atherosclerotic plaques. Recent findings on the inflammatory actions of platelets have established the potential for a previously unrecognized biologic role for platelets in inflammation and vascular injury, and have opened new perspectives in the comprehension of the pathogenetic mechanism(s) of atherosclerosis. Stimulated platelets actively synthesize proinflammatory cytokines (e.g., CD40L, IL-1beta) and are able to release chemokines (i.e., platelet factor-4, RANTES) which have been all involved in the inflammatory process associated with hypercholesterolemia. This review will summarize the present understanding of the interplay between hypercholesterolemia, inflammation and platelet activation in the development and progression of atherosclerosis, and we also discuss the effects of lipid-lowering treatment on these phenomena.

Animals↗

PubMed1991

Relationship of metabolic control and body weight to hypercholesterolemia in NIDDM patients with apolipoprotein E4.

OBJECTIVE: We previously reported that non-insulin-dependent diabetes mellitus (NIDDM) patients with apolipoprotein E4 (apoE4) are more susceptible to hypercholesterolemia. The purpose of this study was to clarify whether metabolic control or body weight is related to hypercholesterolemia in NIDDM patients with apoE4. RESEARCH DESIGN AND METHODS: Two hundred forty NIDDM patients with apoE4 or apoE3/3 who had either hypercholesterolemia or normolipidemia were studied. ApoE phenotypes were determined by isoelectric focusing method. RESULTS: The apoE4-carrying NIDDM patients with hypercholesterolemia (n = 39) showed significantly higher fasting plasma glucose (8.4 vs. 7.2 mM, P less than 0.05), HbA1 (9.3 vs. 8.1%, P less than 0.05), and percentage of ideal body weight values (116 vs. 102%, P less than 0.01) than the apoE4-carrying NIDDM patients with normolipidemia (n = 26), whereas there was no significant difference in their levels between the apoE3/3-carrying NIDDM patients with hypercholesterolemia (n = 47) and normolipidemia (n = 128). CONCLUSIONS: In addition to our previous finding, this study indicates that hypercholesterolemia in apoE4-carrying NIDDM patients may be more closely related to poor metabolic control and increased percentage of ideal body weight.

Adult↗

PubMed2006

Hypercholesterolemia and smoking habits of Lithuanian military personnel.

OBJECTIVE: To investigate the prevalence of risk factors for cardiovascular disease, namely, hypercholesterolemia and current smoking, among 25- to 54-year-old men and women among Lithuanian active duty military personnel. METHODS: Serum cholesterol levels were measured enzymatically for 200 persons (126 men and 74 women). Interviews regarding smoking habits were performed for 82.5% of those persons (98 men and 67 women). RESULTS: Hypercholesterolemia (total cholesterol level of > or = 6.2 mmol/L) was determined for 45.2% of men and 40.5% of women. After distribution of men and women into three age groups (25-34, 35-44, and 45-54 years), it was determined that the rate of hypercholesterolemia increased with age (among groups of men, 29.6%, 46.7%, and 74.0%; among groups of women, 18.8%, 51.5%, and 40.0%, respectively). The proportion of current smokers among men was 2.6 times higher than that among women (45.9% vs. 17.9%; p < 0.001). The highest rate of current smoking was in the 35- to 44-year group of men (64.5%). The coexistence of hypercholesterolemia and current smoking among men was 3.1 times higher than that among women (23.5% vs. 7.5%; p < 0.01). The highest rates of current smoking with hypercholesterolemia were in the 35- to 44-year and 45- to 54-year groups of men (32.2% and 31.8%, respectively). CONCLUSION: The data demonstrated a relatively high rate (32.1%) of coexistence of two independent risk factors for cardiovascular disease (hypercholesterolemia and current smoking) among men 35 to 54 years of age from Lithuanian military personnel.

Adult↗