Wetenschappelijk onderzoek over aderverkalking (atherosclerose)

1. Glycation and oxidation: a role in the pathogenesis of atherosclerosis
   Glycoxidation is of greatest significance in long-lived proteins such as collagen. In these proteins, glycoxidation products, believed to be atherogenic, accumulate with advancing age: in diabetes, their rate of accumulation is accelerated. Inhibition of glycation, oxidation, and glycoxidation may form the basis of future antiatherogenic strategies in both diabetic and nondiabetic individuals.
2. Glucose control in diabetes
   Glycated haemoglobin at baseline is a significant predictor of retinopathy, as well as proteinuria, amputation and survival.
3. TAGE (toxic AGEs) theory in diabetic complications
   Diabetic complication is a leading cause of acquired blindness, end-stage renal failure, a variety of neuropathies and accelerated atherosclerosis. Chronic hyperglycemia is initially involved in the pathogenesis of diabetic micro- and macro-vascular complications via various metabolic derangements. High glucose increased production of various types of advanced glycation end-products (AGEs). Recently, we found that glyceraldehyde-derived AGEs (AGE-2) play an important role in the pathogenesis of angiopathy in diabetic patients.
4. Advanced glycation endproducts--role in pathology of diabetic complications
   Hyperglycaemia has an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation endproducts (AGEs) in body tissues. Protein glycation and AGE are accompanied by increased free radical activity that contributes towards the biomolecular damage in diabetes. This review introduces the chemistry of glycation and AGEs and examines the mechanisms by which they mediate their toxicity. The role of AGEs in the pathogenesis of retinopathy, cataract, atherosclerosis, neuropathy, nephropathy, diabetic embryopathy and impaired wound healing are considered.
5. Advanced glycation end-products and the progress of diabetic vascular complications
   Epidemiological studies have confirmed that hyperglycemia is the most important factor in the onset and progress of vascular complications, both in Type 1 and 2 diabetes mellitus. The formation of advanced glycation end-products (AGEs) correlates with glycemic control. The AGE hypothesis proposes that accelerated chemical modification of proteins by glucose during hyperglycemia contributes to the pathogenesis of diabetic complications including nephropathy, retinopathy, neuropathy and atherosclerosis.
6. Glycation and oxidation: a role in the pathogenesis of atherosclerosis
   Reactions involving glycation and oxidation of proteins and lipids are believed to contribute to atherogenesis. Glycation, the nonenzymatic binding of glucose to protein molecules, can increase the atherogenic potential of certain plasma constituents, including low-density lipoprotein (LDL).
7. Pathophysiological concentrations of glucose promote oxidative modification of low density lipoprotein by a superoxide-dependent pathway
   These findings indicate that glucose enhances LDL lipid peroxidation by an oxidative pathway involving superoxide and raise the possibility that the chronic hyperglycemia of diabetes accelerates lipoprotein oxidation, thereby promoting diabetic vascular disease.

1. Pathogenesis of vascular disease in hyperhomocysteinaemia
   Accumulating evidence suggests that hyperhomocysteinaemia leads to endothelial injury and dysfunction, mediated by free radicals generated during the oxidation of homocysteine. Homocysteine also stimulates the proliferation of vascular smooth-muscle cells and inhibits the growth of vascular endothelial cells. Elevated homocysteine levels may also promote thrombosis by increased generation of thrombin.
2. Homocysteine and arterial disease. Experimental mechanisms
   Current research supports a role for homocysteine (H(e))-mediated endothelial damage and endothelial dysfunction. This mechanism appears to be a key factor in subsequent impaired endothelial-dependent vasoreactivity and decreased endothelium thromboresistance. These consequences may predispose hyperhomocysteinemic vessels to the development of increased atherogenesis.
3. Protein homocysteinylation: a new mechanism of atherogenesis?
   Studies performed during the last two decades suggest that the atherogenic effect of homocysteine may be accounted for by homocysteine thiolactone (HCTL). Homocysteinylation results in the incorporation of additional thiol groups which may alter the physicochemical properties and biological activity of proteins. In particular, homocysteinylation of low-density lipoproteins (LDLs) increases their susceptibility to oxidation and accelerates their uptake by macrophages.
4. Enhancement by Homocysteine of Plasminogen Activator Inhibitor-1 Gene Expression and Secretion from Vascular Endothelial and Smooth Muscle Cells
   Enhancement by In order to elucidate the relationship between homocysteine and the fibrinolytic system, we examined the effect of homocysteine on plasminogen activator inhibitor-1 (PAI-1) and tissue-type plasminogen activator (tPA) gene expression and protein secretion in cultured human vascular endothelial and smooth muscle cells in vitro. These results suggests that hyperhomocysteinemia-induced atherosclerosis and/or thrombosis may be caused by homocysteine-induced stimulation of PAI-1 gene expression and secretion in the vasuculatures by a mechanism independent from paracrine-autocrine activity of TGF and TNF.
5. Homocyst(e)ine, Diet, and Cardiovascular Diseases A Statement for Healthcare Professionals From the Nutrition Committee, American Heart Association
   Homocysteine is a sulfur-containing amino acid, rapidly oxidized in plasma to the disulfides homocystine and cysteine-homocysteine (Figure 1 displays factors involved in the metabolism of homocysteine, including its metabolic relationship to methionine. Although dietary intake of total protein and methionine does not correlate significantly with blood homocyst(e)ine, a single dose of oral methionine (100 mg/kg body weight) can elevate homocyst(e)ine levels, and as described further below, this has been used as a diagnostic test to detect disordered homocyst(e)ine metabolism. Because variable changes in homocyst(e)ine levels have been observed postprandially, it is customary to obtain measurements in the fasting state. Normal levels of fasting plasma homocyst(e)ine are considered to be between 5 and 15 µmol/L. Moderate, intermediate, and severe hyperhomocyst(e)inemia refer to concentrations between 16 and 30, between 31 and 100, and >100 µmol/L, respectively.
6. Plasma homocysteine affects fibrin clot permeability and resistance to lysis in human subjects
   Homocysteine (Hcy) is a risk factor for thrombosis. Our results indicate that plasma tHcy predicts clot permeation and susceptibility to fibrinolysis in healthy men and CAD patients. Our data are consistent with a mechanism of thrombosis in hyperhomocysteinemia, which involves modification of fibrinogen by Hcy-thiolactone.
7. Modification of fibrinogen by homocysteine thiolactone increases resistance to fibrinolysis: a potential mechanism of the thrombotic tendency in hyperhomocysteinemia
   Thus, modification of lysines in fibrinogen could plausibly lead to impaired fibrinolysis. We hypothesize that the modification of lysine by Hcys thiolactone might occur in vivo, lead to abnormal resistance of clots to lysis, and thereby contribute to the prothrombotic state associated with homocysteinemia.

1. Low Density Lipoprotein Oxidation and Its Pathobiological Significance
   The addition of antioxidants to the culture medium completely blocked cell-induced modification, and the changes induced by the cells could be duplicated by incubating LDL in the presence of transition metals in the absence of cells. Thus, oxidative modification induced by cells appeared to be a biologically plausible modification of LDL that could account for foam cell formation and the initiation, or at least acceleration, of the atherosclerotic process.
2. Is Atherosclerosis in Diabetes and Impaired Fasting Glucose Driven by Elevated LDL Cholesterol or by Decreased HDL Cholesterol?
   The low HDL cholesterol/high triglyceride pattern is associated with the degree of hyperglycemia. In coronary patients with type 2 diabetes, this pattern correlates with the prevalence of CAD and significantly predicts the incidence of vascular events.
3. Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes
   It is concluded that LDL size is the strongest marker for clinically apparent as well as non-apparent atherosclerosis in diabetes type 2.
4. LDL Particle Size Distribution Is Associated With Carotid Intima-Media Thickness in Healthy 50-Year-Old Men
   Results of cross-sectional and prospective studies have suggested that small, dense low-density lipoprotein (LDL) particles predispose to coronary heart disease. In contrast, the plasma concentration of the predominant small, dense LDL particle subfraction (LDL-III; particle size, 22.5 to 23.5 nm) correlated strongly with CCA IMT (r=0.42, P<0.001).
5. Low-density lipoprotein size and cardiovascular prevention
   Low-density lipoprotein (LDL) size appears to be an important predictor of cardiovascular events and progression of coronary artery disease, and the predominance of small, dense LDL has been accepted as an emerging cardiovascular risk factor by the National Cholesterol Education Program Adult Treatment Panel III.
6. Usefulness of low-density lipoprotein particle size measurement in cardiovascular disease prevention
   Cardiovascular disease is largely explained by the traditional risk factors, but there are several novel risk factors that have been shown to predict cardiovascular morbidity. Knowing the LDLPS could alter subsequent therapeutic recommendations for most patients who have reached target lipid values.
7. Epidemiologic aspects of lipid abnormalities
   It is concluded that increasing emphasis should be placed on the TC/HDL cholesterol ratio in epidemiologic analyses and in monitoring patients on therapy for dyslipidemia.
8. Risk determination of dyslipidemia in populations characterized by low levels of high-density lipoprotein cholesterol
   In populations at risk for CHD caused by low HDL-C, qualification of subjects for treatment based on either the TC/HDL-C ratio or LDL-C thresholds identifies more high-risk subjects for treatment than LDL-C threshold values alone, and use of the ratio, instead of risk tables, simplifies the approach for physicians
9. How high-density lipoprotein protects against the effects of lipid peroxidation
   The protective effect of HDL against the development of atherosclerosis appears to be multifaceted involving a number of mechanisms. One of the major mechanisms is, however, the ability of HDL to decrease, directly or indirectly, the lipid peroxidation of LDL.
10. Paraoxonase and Atherosclerosis
    There is considerable evidence that the antioxidant activity of high density lipoprotein (HDL) is largely due to the paraoxonase-1 (PON1) located on it. Experiments with transgenic PON1 knockout mice indicate the potential for PON1 to protect against atherogenesis. This protective effect of HDL against low density lipoprotein (LDL) lipid peroxidation is maintained longer than is the protective effect of antioxidant vitamins and could thus be more important.
11. Decreased Atherosclerotic Lesion Formation in Human Serum Paraoxonase Transgenic Mice
    Serum paraoxonase (PON1), an enzyme carried on HDL, inhibits LDL oxidation, and in human population studies, low PON1 activity is associated with atherosclerosis.
12. Paraoxonases and cardiovascular diseases: pharmacological and nutritional influences
    The elucidation of PON1 structure and its active center has enabled a better understanding of its mechanism of action, including its physio-pathological substrate(s). Some drugs and nutrients including dietary antioxidants and polyphenols considerably increase the activities of paraoxonases which, in turn, can reduce oxidative stress and atherosclerosis development.
13. Hypercholesterolemia and Hypertension Have Synergistic Deleterious Effects on Coronary Endothelial Function
    These results suggest that HC and HT have a synergistic deleterious effect on coronary endothelial function, associated with increased oxidative stress. This interaction may contribute to the increased incidence of coronary heart disease and cardiac events seen when HC and HT coexist. Furthermore, chronic antioxidant supplementation significantly improved coronary artery vasoreactivity.
14. Role of the immune response in atherosclerosis and acute coronary syndromes
    The first steps of atherogenesis occur very early, already during the fetal life. Those arterial segments that are subjected to the initiating causes (including hemodynamic stress) show altered endothelial permeability and allow the infiltration of macromolecules, like lipoproteins, in the subintimal space.
15. Macrophage activation in atherosclerosis: pathogenesis and pharmacology of plaque rupture
    Macrophages are recruited and activated by many signals and have an impressive armamentarium of molecules to promote tissue damage. Macrophage-activation stimuli associated with atherosclerotic risk factors include oxidised low density lipoprotein (oxLDL, "bad cholesterol"), advanced glycosylation end products (AGEs) of diabetes, angiotensin II and endothelin.

1. Emerging relations between infectious diseases and coronary artery disease and atherosclerosis
   Cardiovascular disease is the leading cause of death in developed countries. The cause is multifactorial. A substantial proportion of patients with coronary artery disease (CAD) do not have traditional risk factors. Infectious diseases may play a role in these cases, or they may intensify the effect of other risk factors. The association of CAD and Chlamydia pneumoniae infection is firmly established, but causality is yet to be proven. The link with other infectious agents or conditions, such as cytomegalovirus, herpes simplex virus, Helicobacter pylori and periodontitis, is more controversial. Cytomegalovirus infection is more strongly linked than native CAD to coronary artery restenosis after angioplasty and to accelerated CAD after cardiac transplantation. However, new data on this topic are appearing in the literature almost every month. The potential for novel therapeutic management of cardiovascular disease and stroke is great if infection is proven to cause or accelerate CAD or atherosclerosis. However, physicians should not "jump the gun" and start using antibiotic therapy prematurely for CAD. The results of large randomized clinical trials in progress will help establish causality and the benefits of antimicrobial therapy in CAD.
2. Chlamydia pneumoniae infection as a risk factor in acute myocardial infarction
   While early observations on the possible connection between chlamydia and arteriosclerosis remain unnoticed, it was found recently that in acute myocardial infarction (AMI) a sero response to an epitope of chlamydial lipopolysaccharide (LPS) could be demonstrated in about 70% of cases.
3. Chronic Chlamydia pneumoniae infection as a risk factor for coronary heart disease in the Helsinki Heart Study
   The results suggest that chronic C. pneumoniae infection may be a significant risk factor for the development of coronary heart disease.
4. Demonstration of Chlamydia pneumoniae in atherosclerotic lesions of coronary arteries
   C. pneumoniae was detected in coronary artery atheromas by immunocytochemistry (15/36) and by polymerase chain reaction (PCR) (13/30) in 20 of 36 autopsy cases from Johannesburg, South Africa. These findings support the seroepidemiologic studies and offer further evidence that C. pneumoniae may be involved in the atherosclerotic process.
5. Systemic effects of periodontitis: epidemiology of periodontal disease and cardiovascular disease
   As others before us, we conclude that the cumulative evidence presented above supports, but does not prove, a causal association between periodontal infection and atherosclerotic cardiovascular disease or its sequelae.

1. Hormone replacement therapy: estrogen and progestin effects on plasma C-reactive protein concentrations
   HRT can increase CRP levels in healthy women, and both the estrogen and the progestin component are of importance for the change. Whether the increase in CRP levels only reflects a changed steady-state metabolism is unknown. However, the clinical significance should be viewed from the perspective of changes in other inflammatory risk markers of importance for the evolution of cardiovascular disease.
2. Effect of Postmenopausal Hormones on Inflammation-Sensitive Proteins
   Postmenopausal hormones rapidly increased the concentration of the inflammation factor C-reactive protein. Such an effect may be related to adverse early effects of estrogen therapy. In contrast, hormones reduced the concentration of soluble E-selectin, and this might be considered an anti-inflammatory effect. Because PEPI was not designed to assess clinical endpoints, studies of the impact of hormone-mediated changes in inflammation on risk of subsequent coronary events are needed.

1. Mortality from tobacco in developed countries: indirect estimation from national vital statistics.
   At present just under 20% of all deaths in developed countries are attributed to tobacco, but this percentage is still rising, suggesting that on current smoking patterns just over 20% of those now living in developed countries will eventually be killed by tobacco (ie, about a quarter of a billion, out of a current total population of just under one and a quarter billion).
2. The effects of tobacco smoke on the homocysteine level--a risk factor of atherosclerosis
   Homocysteine may promote atherogenesis and thrombogenesis. There is evidence from case - control and cross-sectional cohort studies that there is a positive association between plasma homocysteine levels and coronary artery disease, cerebrovascular disease and peripheral vascular disease. There is also some evidence that certain life-style factors such as cigarette smoking may affect homocysteine levels. In this work is presented a review of recent opinion about the influence of tobacco smoking on homocysteine levels.

1. Coronary calcium as an atherosclerosis marker
   Several clinical studies have shown how the amount of coronary calcifications correlates to the coronary plaque burden.
2. Coronary calcium scanning
   Coronary artery calcium has been shown to be highly specific for atherosclerosis, occurring only in the intima of the coronary arteries. There is evidence to show that elevated coronary calcium scores are predictive of cardiovascular events, both independently of and incrementally to conventional cardiovascular risk factors.
3. Atherosclerosis imaging and calcified plaque: coronary artery disease risk assessment
   Over the last decade, there has been increased recognition that atherosclerosis imaging adds greatly to the ability to identify patients at high risk for cardiac events. Technologies such as electron beam computed tomography and carotid intimal media thickness have contributed significantly to our understanding of the prevalence of preclinical atherosclerosis and its consequences. Accurate measurement of subclinical coronary atherosclerosis should significantly improve the accuracy of global cardiovascular risk prediction and allow for tracking of atherosclerosis burden as well as better prediction of future cardiovascular events.
4. Calcification in coronary artery disease can be reversed by EDTA-tetracycline long-term chemotherapy
   Atherosclerosis is a complex process with multiple mechanisms and factors contributing to its initiation and progression. Detection and quantification of coronary artery calcium (CAC) scores with electron beam tomography has been shown to correlate with obstructive and nonobstructive coronary artery disease (CAD). In conclusion, CAC scores decreased during ComET therapy trial in most CAD patients inferring regression of calcified coronary artery plaque volume. The patients tolerated the therapy well and their angina and lipid profiles improved. Further treatment trials for long term therapy with matched controls are warranted.

1. The role of the platelet in the pathogenesis of atherothrombosis
   Platelet adhesion, activation, and aggregation at sites of vascular endothelial disruption caused by atherosclerosis are key events in arterial thrombus formation.Platelet aggregation, mediated primarily by interaction between the activated platelet GP IIb/IIIa receptor and its ligands, fibrinogen and vWF, results in the formation of a platelet-rich thrombus.
2. Platelets in atherothrombosis
   Atherosclerosis is a diffuse, systemic disease that affects the coronary, cerebral, and peripheral arterial trees. Disruption of atherosclerotic plaques leads to thrombus formation and arterial occlusion. This unpredictable and potentially life-threatening atherothrombotic sequence underlies clinical events such as angina, myocardial infarction, transient ischemic attacks, and stroke.
3. Atherothrombosis: epidemiology, pathophysiology, and prevention
   Ischemic cerebrovascular, coronary, and peripheral arterial disease can be regarded as diverse manifestations of a common underlying systemic pathology, namely atherothrombosis. Secondary prevention of an ischemic event in an affected arterial bed confers the added benefit of primary prevention against potential ischemic events in other arterial beds.
4. Plaque pathology and coronary thrombosis in the pathogenesis of acute coronary syndromes
   Coronary atherosclerosis is by far the most frequent cause of ischemic heart disease and plaque disruption with superimposed thrombosis is the main cause of the acute coronary syndromes of unstable angina, myocardial infarction, and sudden coronary death. The risk for plaque disruption depends more on plaque vulnerability (plaque type) than on degree of stenosis (plaque size). Therefore, we have to focus on plaque composition and vulnerability to rupture and plaque thrombogenicity rather than on plaque size and stenosis severity.

1. Fibrinogen and silent atherosclerosis in subjects with cardiovascular risk
   While the presence of atherosclerosis was significantly related to age, current smoking, systolic pressure, LDL cholesterol, and fibrinogen levels, the extent of atherosclerosis was related to age and triglyceride and fibrinogen levels. Multiple regression analysis indicated independent associations between fibrinogen and the presence and extent of atherosclerosis. Plaque prevalence was significantly more pronounced with increasing tertile of fibrinogen levels. The odds ratio of the upper to lower fibrinogen tertiles for the presence of plaque was 1.6 (95% confidence interval, 1.4 to 1.8) and 1.4 (95% confidence interval, 1.2 to 1.7) for its extent. Adjustment for other risk factors slightly reduced the association between fibrinogen and atherosclerosis
2. Prognostic Influence of Increased Fibrinogen and C-Reactive Protein Levels in Unstable Coronary Artery Disease
   Increased levels of both fibrinogen and C-reactive protein are associated with a worse outcome in patients with unstable coronary artery disease. The increased risk associated with elevated fibrinogen levels is independent of, and additive to, the prognostic influence of myocardial damage.
3. A prospective study of fibrinogen and risk of myocardial infarction in the physicians’ health study
   Among these apparently healthy U.S. male physicians, fibrinogen is associated with increased risk of future MI independent of other coronary risk factors, atherogenic factors such as lipids and antithrombotics such as aspirin.
4. Fibrinogen, fibrin and fibrin degradation products in relation to atherosclerosis
   There seems little doubt that fibrin deposition can both initiate atherogenesis and contribute to the growth of plaques. Epidemiological studies indicate that increased levels of fibrinogen and clotting activity are associated with accelerated atherosclerosis.

1. C-reactive protein, inflammation, and coronary risk
   Epidemiologic data demonstrate an association between the inflammatory marker hs-CRP and risk for future cardiovascular morbidity and mortality among those at high risk or with documented vascular disease. Moreover, a series of prospective studies provides consistent data documenting that mild elevation of baseline levels of hs-CRP among apparently healthy individuals is associated with higher long-term risk for future cardiovascular events. Among men and women, this predictive capacity of hs-CRP is independent of traditional cardiovascular risk factors and offers a prognostic advantage over measurement of lipids alone.
2. Association of coronary plaque rupture and atherosclerotic inflammation
   These results support the concept that inflammation in the fibrous cap is particularly associated with plaque rupture.
3. C-reactive protein: a critical update
   In the mid 1990s, immunoassays for C-reactive protein (CRP), with greater sensitivity than those previously in routine use, revealed that increased CRP values, even within the range previously considered normal, strongly predict future coronary events. These findings triggered widespread interest, especially, remarkably, in the US, where the clinical use of CRP measurement had been largely ignored for about 30 years. CRP production is part of the nonspecific acute-phase response to most forms of inflammation, infection, and tissue damage and was therefore considered not to provide clinically useful information. Indeed, CRP values can never be diagnostic on their own and can only be interpreted at the bedside, in full knowledge of all other clinical and pathological results. However, they can then contribute powerfully to management, just as universal recording of the patient’s temperature, an equally nonspecific parameter, is of great clinical utility.
4. Elevation of C-reactive protein in "active" coronary artery disease
   The data demonstrate increased levels of an acute phase reactant in unstable angina. These findings suggest that an inflammatory component in "active" angina may contribute to the susceptibility of these patients to vasospasm and thrombosis.
5. Serum C-reactive protein and fibrinogen concentrations and self-reported angina pectoris and myocardial infarction: findings from National Health and Nutrition Examination Survey III
   These cross-sectional data showed a significant positive association between C-reactive protein concentration and myocardial infarction but not self-reported angina pectoris in the U.S. population.
6. Prognostic Influence of Increased C-Reactive Protein and Fibrinogen Levels in Ischemic Stroke
   Increased levels of CRP are associated with a worse outcome in patients with ischemic stroke. The increased risk associated with elevated CRP levels is independent of the prognostic influence of fibrinogen.
7. Plasma Concentration of C-Reactive Protein and Risk of Developing Peripheral Vascular Disease
   These prospective data indicate that among apparently healthy men, baseline levels of CRP predict future risk of developing symptomatic PAD and thus provide further support for the hypothesis that chronic inflammation is important in the pathogenesis of atherothrombosis.
8. C Reactive protein and its relation to cardiovascular risk factors: a population based cross sectional study
   The body's response to inflammation may play an important part in influencing the progression of atherosclerosis. The association of C reactive protein concentration with coronary heart disease needs testing in prospective studies.
9. Relation of C-reactive protein and coronary heart disease in the MRFIT nested case-control study. Multiple Risk Factor Intervention Trial
   There was a significant association between available distribution of C-reactive protein and subsequent coronary heart disease mortality. This is the first prospective study in "healthy but high risk individuals" to document the relation between C-reactive protein and coronary heart disease mortality.
10. C-Reactive Protein and Other Markers of Inflammation in the Prediction of Cardiovascular Disease in Women
    The addition of the measurement of C-reactive protein to screening based on lipid levels may provide an improved method of identifying women at risk for cardiovascular events.
11. C-Reactive Protein Adds to the Predictive Value of Total and HDL Cholesterol in Determining Risk of First Myocardial Infarction
    Among 14 916 apparently healthy men participating in the Physicians' Health Study, baseline levels of CRP, TC, and HDL-C were measured among 245 study subjects who subsequently developed a first MI (cases) and among 372 subjects who remained free of cardiovascular disease during an average follow-up period of 9 years (controls). In univariate analyses, high baseline levels of CRP, TC, and TC:HDL-C ratio were each associated with significantly increased risks of future MI (all P values <0.001).

1. Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence
   Results of epidemiologic studies suggest that moderately elevated plasma or serum homocyst(e)ine levels are prevalent in the general population and are associated with an increased risk for cardiovascular disease, independent of classic cardiovascular risk factors. Simple, inexpensive, nontoxic therapy with folic acid, vitamin B6, and vitamin B12 reduces plasma homocyst(e)ine levels. Although the association between homocyst(e)ine levels and cardiovascular disease is generally strong and biologically plausible, the data from the prospective studies are less consistent. In addition, epidemiologic observations of an association between hyperhomocyst(e)inemia and cardiovascular risk do not prove the existence of a causal relation. Therefore, the effectiveness of folate, vitamin B6, and vitamin B12 in reducing cardiovascular morbidity and mortality requires rigorous testing in randomized clinical trials. Several such trials are under way; their results may greatly affect cardiovascular morbidity and mortality, given the simplicity and low cost of vitamin therapy.
2. Hyperhomocysteinemia Confers an Independent Increased Risk of Atherosclerosis in End-Stage Renal Disease and Is Closely Linked to Plasma Folate and Pyridoxine Concentrations
   Patients with a homocysteine concentration in the upper two quintiles (>27.8 µmol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P=.007) of vascular complications.
3. Plasma total homocysteine, B vitamins, and risk of coronary atherosclerosis
   Furthermore, there was a significant linear trend of increasing fasting tHcy with increasing number of occluded arteries (P=.01), correcting for sex, age, and other potential confounders. Our data show a positive association between plasma tHcy and risk of severe coronary atherosclerosis, of similar strength for fasting and postload tHcy levels. The data suggest that the association exists over a wide range of tHcy levels, without a clear cutoff point below which there is no increased risk.
4. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes
   A 5-mumol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements.
5. Effect of homocysteine-lowering treatment with folic acid plus vitamin B6 on progression of subclinical atherosclerosis: a randomised, placebo-controlled trial
   Homocysteine-lowering treatment with folic acid plus vitamin B6 in healthy siblings of patients with premature atherothrombotic disease is associated with a decreased occurrence of abnormal exercise electrocardiography tests, which is consistent with a decreased risk of atherosclerotic coronary events.
6. Patients with atherosclerotic vascular disease: how low should plasma homocyst(e)ine levels go?
   Homocyst(e)ine levels above 10.2 micro mol/L are associated with a doubling of coronary risk, and levels above 20 micro mol/L are associated with a 9.9-fold increase in risk compared with levels below 9 micro mol/L.
7. Plasma total homocysteine and cardiovascular and noncardiovascular mortality: the Hordaland Homocysteine Study
   During a median of 4.1 y of follow-up, 162 men and 97 women died. A strong relation was found between plasma tHcy and all-cause mortality. The association was highly significant for noncardiovascular and for cardiovascular causes of death. In a comparison of individuals having tHcy concentrations of 9.0–11.9, 12.0–14.9, 15.0–19.9, or =" src="/math/ge.gif" border=020 µmol/L with individuals having a tHcy concentration <9 µmol/L, adjusted mortality ratios were 1.4, 1.9, 2.3, and 3.6 (P for trend = 0.0002) for noncardiovascular and 1.3, 2.1, 2.6, and 3.5 (P for trend = 0.0002) for cardiovascular causes of death. A tHcy increment of 5 µmol/L was associated with a 49% (95% CI: 28%, 72%) increase in all-cause mortality, a 50% (95% CI: 21%, 85%) increase in cardiovascular mortality (121 deaths), a 26% (95% CI: –2%, 63%) increase in cancer mortality (103 deaths), and a 104% (95% CI: 44%, 289%) increase in noncancer, noncardiovascular mortality (33 deaths).
8. The Hordaland Homocysteine Study: a community-based study of homocysteine, its determinants, and associations with disease
   Significant associations between tHcy and clinical outcomes are usually observed for tHcy levels > 15 micromol/L, but for most conditions, there is a continuous concentration-response relation with no apparent threshold concentration. Overall, the findings from HHS indicate that a raised tHcy level is associated with multiple clinical conditions, whereas a low tHcy level is associated with better physical and mental health.

1. Cardiovascular risk factors: interactive effects of lipids, coagulation and fibrinolysis
   During the last years our knowledge of factors that contribute to the development and progression of this disease has increased markedly. Elevated serum total cholesterol, hypertension and cigarette smoking are "traditional", well-known risk factors. In addition, low serum levels of high density lipoprotein (HDL) cholesterol predispose to development of disease, whereas in epidemiological studies the role of increased triglycerides is more controversial.

1. Polymyalgia, Hypersensitivity Pneumonitis and Other Reactions in Patients Receiving HMG-CoA Reductase Inhibitors
   Since 1980, hydroxy-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have become the most prescribed cholesterol-lowering drugs. Recently we have encountered a series of patients with evidence of hypersensitivity to HMG-CoA reductase inhibitors, or statin drugs. We are reporting our experience with 10 patients: two with potentially life-threatening reactions and one with biopsy evidence of hypersensitivity pneumonitis. We are aware of only two previous cases of interstitial lung disease in association with statin medications.
2. Statins and peripheral neuropathy
   Within the past 3 years seven cases of reversible peripheral neuropathy apparently caused by statins have been reported. Here we report seven additional cases associated with long-term statin therapy, in which other causes of neuropathy were thoroughly excluded. The neuropathy was in all cases axonal and with affection of both thick and thin nerve fibers. The symptoms of neuropathy persisted during an observation period lasting from 10 weeks to 1 year in four cases after statin treatment had been withdrawn. We suggest that long-term statin treatment may be associated with chronic peripheral neuropathy.
3. Toxic liver damage caused by HMG-CoA reductase inhibitor
   Therefore, when prescribing a HMG-CoA-reductase inhibitor, the possibility of liver damage should be mentioned and regular checks of the transaminase values should be performed.
4. Development of tachyphylaxis among patients taking HMG CoA reductase inhibitors
   All other statins, at all doses reviewed, showed evidence of tachyphylaxis. LDL cholesterol tachyphylaxis appeared to be a unique response to prolonged use of long half-life atorvastatin therapy at exposure dosages.
5. Acute cholestatic hepatitis during simvastatin administration
   Simvastatin, recently introduced in clinical practice for pharmacological treatment of hypercholesterolemia, has been found to cause minor and reversible elevations of serum transaminases. We report a case of acute cholestatic hepatitis during simvastatin therapy. Clinical, biochemical, immunological, and histological findings were consistent with a simvastatin-induced liver damage through an immunological-mediated mechanism. This case suggests a careful monitoring of liver function tests during simvastatin therapy, and caution in continuing simvastatin administration when elevations of serum transaminases take place.
6. Recurrent acute pancreatitis during pravastatin-therapy
   We present a 60-years-old male who developed twice an acute pancreatitis while being treated with pravastatin.
7. Atorvastatin decreases the coenzyme Q10 level in the blood of patients at risk for cardiovascular disease and stroke
   Even brief exposure to atorvastatin causes a marked decrease in blood CoQ(10) concentration. Widespread inhibition of CoQ(10) synthesis could explain the most commonly reported adverse effects of statins, especially exercise intolerance, myalgia, and myoglobinuria.
8. The clinical use of HMG CoA-reductase inhibitors and the associated depletion of coenzyme Q10. A review of animal and human publications
   The depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials.
9. Current lipid management and low cholesterol goal attainment in common daily practice in Spain. The REALITY Study
   The depletion of the essential nutrient CoQ10 by the increasingly popular cholesterol lowering drugs, HMG CoA reductase inhibitors (statins), has grown from a level of concern to one of alarm. With ever higher statin potencies and dosages, and with a steadily shrinking target LDL cholesterol, the prevalence and severity of CoQ10 deficiency is increasing noticeably. An estimated 36 million Americans are now candidates for statin drug therapy. Statin-induced CoQ10 depletion is well documented in animal and human studies with detrimental cardiac consequences in both animal models and human trials.
10. Interstitial lung disease with pleural effusion caused by simvastin
    Simvastin, a HMG-CoA reductase blocker, is used for the treatment of certain forms of hypercholesterolaemia. Simvastin is prescribed to lower high serum levels of cholesterol by inhibiting a specific enzyme, hydroxy-methylglutarylCo-enzym-A (HMG-CoA) reductase. This ultimately leads to an increase of the number of LDL-receptors in the liver, and thus, to a decrease of the serum LDL-cholesterol. We present a patient who developed interstitial lung disease with pleural effusion most probably as a result of the use of Simvastin.
11. Cholesterol lowering trials in coronary heart disease: frequency of citation and outcome
    Lowering serum cholesterol concentrations does not reduce mortality and is unlikely to prevent coronary heart disease. Claims of the opposite are based on preferential citation of supportive trials
12. Cholesterol lowering and mortality: the importance of considering initial level of risk
    OBJECTIVE--To investigate the level of risk of death from coronary heart disease above which cholesterol lowering treatment produces net benefits. CONCLUSION--Currently evaluated cholesterol lowering drugs seem to produce mortality benefits in only a small proportion of patients at very high risk of death from coronary heart disease. Population cholesterol screening could waste resources and even result in net harm in substantial groups of patients. Overall risk of coronary heart disease should be the main focus of clinical guidelines, and a cautious approach to the use of cholesterol lowering drugs should be advocated. Future trials should aim to clarify the level of risk above which treatment is of net benefit.

1. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men
   The base-line plasma concentration of C-reactive protein predicts the risk of future myocardial infarction and stroke. Moreover, the reduction associated with the use of aspirin in the risk of a first myocardial infarction appears to be directly related to the level of C-reactive protein, raising the possibility that antiinflammatory agents may have clinical benefits in preventing cardiovascular disease.
2. Vitamin E plus aspirin compared with aspirin alone in patients with transient ischemic attacks
   We concluded that the combination of vitamin E and a platelet antiaggregating agent (eg, aspirin) significantly enhances the efficacy of the preventive treatment regimen in patients with transient ischemic attacks and other ischemic cerebrovascular problems.
3. Low-dose aspirin and vitamin E in people at cardiovascular risk: a randomised trial in general practice. Collaborative Group of the Primary Prevention Project
   In women and men at risk of having a cardiovascular event because of the presence of at least one major risk factor, low-dose aspirin given in addition to treatment of specific risk factors contributes an additional preventive effect, with an acceptable safety profile. The results on vitamin E's cardiovascular primary preventive efficacy are not conclusive per se, although our results are consistent with the negative results of other large published trials on secondary prevention.
4. Personal health habits of American cardiologists
   Aspirin and statins were each taken daily by about 1/3 of the participants.
5. Aspirin and coronary artery disease
   Aspirin, the prototype antiplatelet agent, covalently and irreversibly inhibits cyclooxygenase (COX) and thus inhibits platelet thromboxane (TX) A(2) biosynthesis.
6. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis
   The antithrombotic action of aspirin (acetylsalicylic acid) is due to inhibition of platelet function by acetylation of the platelet cyclooxygenase (COX) at the functionally important amino acid serine529.

1. Group B vitamins as new variables related to the cardiovascular risk
   The nutritional status and plasma concentrations of some group B vitamins, namely vitamin B6, vitamin B12 and folic acid, have recently emerged as inverse correlates of cardiovascular risk, and several experimental and clinical studies, these latter mostly retrospective and case-control studies, indicate a defect of such vitamins as capable of promoting the progression of atherosclerosis.
2. Vitamin supplements and cardiovascular risk: review of the randomized trials of homocysteine-lowering vitamin supplements
   After standardization for a pretreatment homocysteine concentration of 12 micromol/L and folate concentration of 12 nmol/L (approximate average concentrations for western populations), dietary folic acid reduced homocysteine levels by 25% (95% confidence interval [CI]: 23 to 28%) with similar effects in a daily dosage range of 0.5 to 5 mg. Vitamin B12 (mean 0.5 mg) produced an additional reduction in blood homocysteine of 7%, whereas vitamin B6 (mean 16.5 mg) did not have any significant effect. Hence, in typical populations, daily supplementation with both 0.5 to 5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce homocysteine levels by one quarter to one third (from about 12 micromol/L to about 8 to 9 micromol/L). Large-scale randomized trials of such regimens are now required to determine whether lowering homocysteine levels by folic acid and vitamin B12, with or without added vitamin B6, reduces the risk of vascular disease.
3. Folate and vitamin B6 from diet and supplements in relation to risk of coronary heart disease among women
   These results suggest that intake of folate and vitamin B6 above the current recommended dietary allowance may be important in the primary prevention of CHD among women.
4. Low Circulating Folate and Vitamin B6 Concentrations
   Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.
5. Vitamins B6, B12, and Folate: Association with Plasma Total Homocysteine and Risk of Coronary Atherosclerosis
   Lower levels of folate and vitamin B6 confer an increased risk of atherosclerosis. Clinical trials are now required to evaluate the effect of treatment with these vitamins in the primary and secondary prevention of vascular diseases.
6. Role of vitamins B6, B12 and folic acid on hyperhomocysteinemia in a Pakistani population of patients with acute myocardial infarction
   Pakistani people belong to an ethnic group which has the highest rate of coronary artery disease (CAD). Substantial nutritional deficiencies of these three vitamins along with mild hyperhomocysteinemia, perhaps through an interplay with the classical cardiovascular risk factors (highly prevalent in this population), could be further aggravating the risk of CAD in the Pakistani population.
7. Homocysteine metabolism and risk of myocardial infarction: relation with vitamins B6, B12, and folate
   These data provide further evidence that plasma homocyst(e)ine is an independent risk factor for myocardial infarction. In this population, folate was the most important determinant of plasma homocyst(e)ine, even in subjects with apparently adequate nutritional status of this vitamin.
8. Folate deficiencies and cardiovascular pathologies
   In addition to the essential role of the intracellular pool of polyglutamates in de novo biosynthesis of deoxyribonucleotides which allow cell growth and division, the reduced and methylated form of folate, N5-methyltetrahydrofolate, is required for the remethylation of homocysteine to methionine.
9. Hyperhomocysteinemia: a risk factor for arterial and venous thrombosis
   Homocysteine is a sulfur-containing amino acid intermediate involved in two metabolic pathways, in the remethylation to methionine and in the transsulfuration to cysteine. Severe hyperhomocysteinemia (> 100 mumol/l) is found in congenital homocystinuria. Moderate (15-30 mumol/l) or intermediate (> 30-100 mumol/l) hyperhomocysteinemia is caused by defects in genes encoding for enzymes of homocysteine metabolism or by inadequate intake of those vitamins that are involved in homocysteine metabolism (folic acid, cobalmin, and vitamin B6).
10. Lowering blood homocysteine with folic acid-based supplements: meta-analysis of randomised trials
    In conclusion, typically in Western populations, daily supplementation with both 0.5-5 mg folic acid and about 0.5 mg vitamin B12 would be expected to reduce blood homocysteine concentrations by about a quarter to a third (for example, from about 12 micromol/L to 8-9 micromol/L). Large scale randomised trials of such regimens in high risk populations are now needed to determine whether lowering blood homocysteine concentration reduces the risk of vascular disease.

1. Role of vitamin E in preventing the oxidation of low-density lipoprotein
   The fatty acid composition, antioxidants, and the oxidation resistance of the low-density lipoproteins (LDL) from a number of different donors were determined. The oxidation resistance of LDL, as determined in vitro by the duration of the lag-phase in copper ion-induced oxidation, did not correlate with the alpha-tocopherol content of the LDL. By supplementating plasma with vitamin E, the alpha-tocopherol content of LDL could be increased from approximately 9 to 30 mol/mol LDL and also the oxidative resistance increased nearly linearly with increasing alpha-tocopherol content. The results indicate that alpha-tocopherol is an important, yet not the only parameter that determines the oxidation resistance of LDL
2. Effect of dietary antioxidant combinations in humans. Protection of LDL by vitamin E but not by beta-carotene
   Thus, long-term supplementation with large doses of vitamin E alone, but not beta-carotene, conferred increased protection to LDL in in vitro assays of oxidation. These data should be useful in planning therapeutic strategies to test the antioxidant hypothesis in humans.
3. Antioxidants and Atherosclerotic Heart Disease
   Epidemiologic studies have demonstrated an association between increased intake of antioxidant vitamins such as vitamin E and vitamin C and reduced morbidity and mortality from coronary artery disease. This association has been explained on the basis of the "oxidative-modification hypothesis" of atherosclerosis, which proposes that atherogenesis is initiated by oxidation of the lipids in low-density lipoprotein (LDL), also termed lipid peroxidation.
4. The effect of alpha-tocopherol on monocyte proatherogenic activity
   Thus, in addition to the decrease in oxidative stress resulting from AT supplementation, as evidenced by decreased F2-isoprostanes and LDL oxidizability, AT is anti-inflammatory and exerts beneficial antiatherogenic effects on cells crucial in atherogenesis such as monocytes.
5. Vitamin E, oxidative stress, and inflammation
   Based on its antioxidant and anti-inflammatory activities, AT (at the appropriate dose and form) could have beneficial effects on cardiovascular disease in a high-risk population.
6. Anti-inflammatory effects of alpha-tocopherol
   In addition, alpha-tocopherol has been shown to decrease CRP levels in patients with CVD and having related risk factors for CVD (such as diabetes and smoking). Furthermore, pro-inflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1) levels have also been shown to be decreased with alpha-tocopherol supplementation in vivo.
7. Vitamin E Oxidation in Human Atherosclerotic Lesions
   This study may have important implications regarding antioxidant supplements aimed at preventing LDL oxidation and hence atherogenesis.
8. Alpha-tocopherol, an effective inhibitor of platelet adhesion
   Our results suggest that vitamin E may also be an effective antiadhesive agent in vivo.
9. The Effects of Alpha Tocopherol Supplementation on Monocyte Function
   Thus, this study provides novel evidence for an intracellular effect of alpha tocopherol in monocytes that is antiatherogenic.
10. Randomised controlled trial of vitamin E in patients with coronary disease: Cambridge Heart Antioxidant Study (CHAOS)
    We conclude that in patients with angiographically proven symptomatic coronary atherosclerosis, alpha-tocopherol treatment substantially reduces the rate of non-fatal MI, with beneficial effects apparent after 1 year of treatment. The effect of alpha-tocopherol treatment on cardiovascular deaths requires further study
11. Vitamin E and heart disease: Basic science to clinical intervention trials
    The in vitro, cellular, and animal studies, which are impressive both in quantity and quality, leave no doubt that vitamin E, the most important fat-soluble antioxidant, protects animals against a variety of types of oxidative stress. The hypothesis that links vitamin E to the prevention of cardiovascular disease (CVD) postulates that the oxidation of unsaturated lipids in the low-density lipoprotein (LDL) particle initiates a complex sequence of events that leads to the development of atherosclerotic plaque. This hypothesis is supported by numerous studies in vitro, in animals, and in humans. Vitamin E at the supplemental levels being used in the current trials, 100 to 800 IU/d, is safe, and there is little likelihood that increased risk will be found for those taking supplements. About one half of American cardiologists take supplemental vitamin E, about the same number as take aspirin. In view of the very low risk of reasonable supplementation with vitamin E, and the difficulty in obtaining more than about 30 IU/day from a balanced diet, some supplementation appears prudent now.
12. Alpha tocopherol supplementation decreases serum C-reactive protein and monocyte interleukin-6 levels in normal volunteers and type 2 diabetic patients
    AT supplementation significantly lowered levels of C-reactive protein and monocyte interleukin-6 in all three groups. In conclusion, AT therapy decreases inflammation in diabetic patients and controls and could be an adjunctive therapy in the prevention of atherosclerosis.
13. Tolerance and safety of vitamin E: a toxicological position report
    From numerous publications on the "prophylactic" and "therapeutic" use of vitamin E, it may be concluded that the toxicity of vitamin E is very low. It has been demonstrated in animal experiments that vitamin E has neither mutagenic, teratogenic nor carcinogenic properties. Based on studies in humans, a daily dosage of 100-300 mg vitamin E can be considered harmless from a toxicological point of view. From numerous publications on the "prophylactic" and "therapeutic" use of vitamin E, it may be concluded that the toxicity of vitamin E is very low. It has been demonstrated in animal experiments that vitamin E has neither mutagenic, teratogenic nor carcinogenic properties. Based on studies in humans, a daily dosage of 100-300 mg vitamin E can be considered harmless from a toxicological point of view.
14. Effect of supplementation with vitamin E on LDL oxidizability and prevention of atherosclerosis
    Dose-response studies in humans have reported that 400 IU/day vitamin E increased its levels in plasma two-fold and prolonged the lag time before LDL oxidation. It has been reported that oxidizability of LDL was correlated to the atherosclerotic score of coronary angiography in CHD patients. About 400 IU/day vitamin E, which increases its levels two-fold and prolongs sufficiently the lag time before LDL oxidation, might be beneficial in decreasing the individual risk of CHD.
15. Effect of Supplementary Antioxidant Vitamin Intake on Carotid Arterial Wall Intima-Media Thickness in a Controlled Clinical Trial of Cholesterol Lowering
    Supplementary vitamin E intake appears to be effective in reducing the progression of atherosclerosis in subjects not treated with lipid-lowering drugs while the process is still confined to the arterial wall (early preintrusive atherosclerosis).
16. Vitamin E Consumption and the Risk of Coronary Heart Disease in Men
    These data do not prove a causal relation, but they provide evidence of an association between a high intake of vitamin E and a lower risk of coronary heart disease in men. Public policy recommendations with regard to the use of vitamin E supplements should await the results of additional studies.
17. Vitamin E Consumption and the Risk of Coronary Disease in Women
    Although these prospective data do not prove a cause-and-effect relation, they suggest that among middle-aged women the use of vitamin E supplements is associated with a reduced risk of coronary heart disease. Randomized trials of vitamin E in the primary and secondary prevention of coronary disease are being conducted; public policy recommendations about the widespread use of vitamin E should await the results of these trials.
18. Antioxidant Supplements Block the Response of HDL to Simvastatin-Niacin Therapy in Patients With Coronary Artery Disease and Low HDL
    These favorable responses were blunted by the antioxidants used owing to a striking selective effect on Lp(A-I). This unexpected adverse interaction between antioxidants and lipid therapy may have important implications for the management of CAD.

1. Antioxidant Vitamins C and E Improve Endothelial Function in Children With Hyperlipidemia
   Antioxidant therapy with vitamins C and E restores endothelial function in hyperlipidemic children. Early detection and treatment of endothelial dysfunction in high-risk children may retard the progression of atherosclerosis.
2. Vitamin C intake and mortality among a sample of the United States population
   The relation of the standardized mortality ratio (SMR) for all causes of death to increasing vitamin C intake is strongly inverse for males and weakly inverse for females. Among those with the highest vitamin C intake, males have an SMR (95% confidence interval) of 0.65 (0.52-0.80) for all causes, 0.78 (0.50-1.17) for all cancers, and 0.58 (0.41-0.78) for all cardiovascular diseases; females have an SMR of 0.90 (0.74-1.09) for all causes, 0.86 (0.55-1.27) for all cancers, and 0.75 (0.55-0.99) for all cardiovascular diseases.
3. Vitamin C and risk of death from stroke and coronary heart disease in cohort of elderly people
   In elderly people vitamin C concentration, whether measured by dietary intake or plasma concentration of ascorbic acid, is strongly related to subsequent risk of death from stroke but not from coronary heart disease.
4. Vitamin C as an Antioxidant: Evaluation of Its Role in Disease Prevention
   Vitamin C in humans must be ingested for survival. Vitamin C is an electron donor, and this property accounts for all its known functions. As an electron donor, vitamin C is a potent water-soluble antioxidant in humans. Antioxidant effects of vitamin C have been demonstrated in many experiments in vitro. Human diseases such as atherosclerosis and cancer might occur in part from oxidant damage to tissues.
5. Long-Term Ascorbic Acid Administration Reverses Endothelial Vasomotor Dysfunction in Patients With Coronary Artery Disease
   In patients with CAD, long-term ascorbic acid treatment has a sustained beneficial effect on EDNO action. Because endothelial dysfunction may contribute to the pathogenesis of cardiovascular events, this study indicates that ascorbic acid treatment may benefit patients with CAD.
6. Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease
   Ascorbic acid reverses endothelial vasomotor dysfunction in the brachial circulation of patients with coronary artery disease. These findings suggest that increased oxidative stress contributes to endothelial dysfunction in patients with atherosclerosis and that endothelial dysfunction may respond to antioxidant therapy.
7. Serial coronary angiographic evidence that antioxidant vitamin intake reduces progression of coronary artery atherosclerosis
   These results indicate an association between supplementary vitamin E intake and angiographically demonstrated reduction in coronary artery lesion progression. Verification from carefully designed, randomized, serial arterial imaging end point trials is needed.
8. Vitamin C deficiency and risk of myocardial infarction: prospective population study of men from eastern Finland
   Vitamin C deficiency, as assessed by low plasma ascorbate concentration, is a risk factor for coronary heart disease.
9. Improvement of peripheral endothelial dysfunction by acute vitamin C application: different effects in patients with coronary artery disease, ischemic, and dilated cardiomyopathy
   Acute vitamin C administration restored peripheral endothelial function in patients with CAD to normal values, whereas endothelial function remained attenuated in CHF, in particular in patients with DCM. These results suggest that in patients with CHF, factors other than oxidative stress (eg, cytokines) contribute to the pathologic endothelial function.
10. Relationship of plasma level of vitamin C to mortality from ischemic heart disease
    The present epidemiological data support and extend previous evidence in men and animals. Thus, a poor plasma status of vitamin C (less than 23 microM = 0.4 mg/dl) and/or of cholesterol-standardized vitamin E (less than 20-21.5 microM = 9 mg/l) occurs in westernized countries with an increased risk of IHD. A poor status in the major essential antioxidants may be a hitherto underrated, at least permissive, risk factor of IHD that could, at least in some European countries, substantially complement the previously established risk factors such as hypercholesterolemia.
11. Increased risk of cardiovascular disease at suboptimal plasma concentrations of essential antioxidants: an epidemiological update with special attention to carotene and vitamin C
    For the prolongation of life expectancy and reduction of ischemic heart disease (IHD) dietary guidelines generally recommend lowering saturated mammalian fat with partial replacement by vegetable oils and increasing generously vegetables, legumes, and fruits, which provide more essential antioxidants. Plasma antioxidants as assayed in epidemiological studies of complementary type (ie the cross-cultural MONICA Vitamin Substudy reevaluation considering the "Finland-Factor", the Edinburgh Angina-Control Study, and the Basel Prospective Study) consistently revealed an increased risk of IHD (and stroke) at low plasma concentrations of antioxidants, with the rank order as follows: lipid-standardized vitamin E >> carotene = vitamin C > vitamin A, independently of classical IHD risk factors. Decreasing IHD risk through nutrition may be possible when plasma concentrations have the following values: > 27.5-30.0 mumol vitamin E/L, 0.4-0.5 mumol carotene/L, 40-50 mumol vitamin C/L and 2.2-2.8 mumol vitamin A/L. Thus, previous prudent regimens may now be updated, aiming at an optimal status of all essential and synergistically linked antioxidants.

1. Fibrinolytic and antithrombotic action of bromelain may eliminate thrombosis in heart patients
   It has been established that a bromelain plasminogen activator will produce plasmin in rat experiments. In addition the plasmin cleaves Hageman factor in a way that leads to a strong release of kallikrein but a weak release of thrombin. A possible mechanism is suggested to explain how the body can maintain thrombin at a level too low to cause platelet aggregation but adequate to stimulate release of prostaglandins and enzymes for more than 24 hours from a single dose of the pineapple enzymes. Since bromelain therapy leads to formation of platelets with increased resistance to aggregation, it is obvious that the dominant endogenous prostaglandins being produced must be from the group that increases platelet cyclicAMP levels (prostacyclin, PGE1, etc.). The combination of fibrinolytic and antithrombic properties appear to be effective and two large scale tests on heart patients have shown a practically complete elimination of thrombosis.
2. Bromelain proteases reduce human platelet aggregation in vitro, adhesion to bovine endothelial cells and thrombus formation in rat vessels in vivo
   Bromelain, orally applied at 60 mg/kg body weight, inhibited the thrombus formation in a time dependent manner, the maximum being after 2 hours in 11% of arterioles and 6% of venoles. Intravenous application at 30 mg/kg was slightly more active in reducing thrombus formation in arterioles (13%) and venoles (5%), suggesting that orally applied bromelain is biologically active. These results may help to explain some of the clinical effects observed after bromelain treatment in patients with thrombosis and related diseases.
3. On the pharmacology of bromelain: an update with special regard to animal studies on dose-dependent effects
   Bromelain, a standardized complex of proteases from the pineapple plant, is absorbed unchanged from the intestine of animals at a rate of 40%; in animal experiments it was found to have primarily anti-edema, antiinflammatory, and coagulation-inhibiting effects. These effects are due to an enhancement of the serum fibrinolytic activity and inhibition of the fibrinogen synthesis, as well as a direct degradation of fibrin and fibrinogen. Bromelain lowers kininogen and bradykinin serum and tissue levels and has an influence on prostaglandin synthesis, thus acting antiinflammatory. In in vitro and in animal studies, experimentally induced tumours could be inhibited by bromelain. Although many studies do not give extensive statistical data, the effects of bromelain in animal studies seem to be dose-dependent. Further investigations have to be carried out.
4. Bromelain: biochemistry, pharmacology and medical use
   Bromelain is a crude extract from the pineapple that contains, among other components, various closely related proteinases, demonstrating, in vitro and in vivo, antiedematous, antiinflammatory, antithrombotic and fibrinolytic activities. The claim that bromelain cannot be effective after oral administration is definitely refuted at this time.

1. Role of policosanols in the prevention and treatment of cardiovascular disea
   In summary, policosanols are a promising resource in the prevention and therapy of cardiovascular disease (CVD), but these results need to be confirmed in independent laboratories.
2. Policosanol: a new treatment for cardiovascular disease?
   Policosanol is a mixture of alcohols isolated and purified from sugar cane. Recently, Cuban researchers found 5-20 mg daily of policosanol to be effective at improving serum lipid profiles. Policosanol is believed to decrease total cholesterol (TC), low-density lipoprotein (LDL), and increase high-density lipoprotein (HDL) by inhibiting cholesterol synthesis and increasing LDL processing. Lipid profile improvements are seen in healthy volunteers, patients with type II hypercholesterolemia, type 2 diabetics with hypercholesterolemia, postmenopausal women with hypercholesterolemia, and patients with combined hypercholesterolemia and abnormal liver function tests. Additionally, policosanol has performed equal to or better than simvastatin, pravastatin, lovastatin, probucol, or acipimox with fewer side effects in patients with type II hypercholesterolemia. Policosanol also decreases several other risk factors of cardiovascular disease by decreasing LDL oxidation, platelet aggregation, endothelial damage, and smooth muscle cell proliferation. Furthermore, policosanol decreases progression and increases regression of cardiovascular disease assessed by thallium-labeled myocardial perfusion scintigraphy (TL-MPS) and Doppler-ultrasound, and decreases symptoms of cardiovascular disease assessed by the Specific Activity Scale.
3. Effects of policosanol and pravastatin on lipid profile, platelet aggregation and endothelemia in older hypercholesterolemic patients
   In conclusion, the effects of policosanol (10 mg/day) on lipid profile, platelet aggregation and endothelemia in older patients with type II hypercholesterolemia and high coronary risk are more favorable than those induced by the same doses of pravastatin.
4. Effects of policosanol 20 versus 40 mg/day in the treatment of patients with type II hypercholesterolemia: a 6-month double-blind study
   In conclusion, although the tolerability profile remains excellent, according to the present results policosanol at a dose of 40 mg/day does not offer significant additional cholesterol-lowering efficacy over the 20 mg/day dose.
5. Protective effect of policosanol on atherosclerotic plaque on aortas in monkeys
   These results suggest the policosanol potential benefit on plaque composition and stability and could explain the protective effects of policosanol on atherosclerosis development.
6. Effects of policosanol treatment on the susceptibility of low density lipoprotein (LDL) isolated from healthy volunteers to oxidative modification in vitro
   The present study demonstrated that policosanol administered within its therapeutic dosage for lowering cholesterol (5 and 10 mg day(-1)), decreased the susceptibility of LDL-C to lipid peroxidation in vitro.
7. Effects of policosanol and lovastatin on lipid profile and lipid peroxidation in patients with dyslipidemia associated with type 2 diabetes mellitus
   In conclusion, policosanol and lovastatin administered short term to patients with dyslipidemia secondary to type 2 diabetes were effective in lowering cholesterol and in inhibiting the extent of lipid peroxidation. Policosanol (10 mg/day) was slightly more effective than lovastatin (20 mg/day) in reducing the LDL-C/HDL-C and total cholesterol/HDL-C ratios, in increasing HDL-C levels and in preventing LDL oxidation.
8. Meta-analysis of natural therapies for hyperlipidemia: plant sterols and stanols versus policosanol
   Plant sterols and stanols and policosanol are well tolerated and safe; however, policosanol is more effective than plant sterols and stanols for LDL level reduction and more favorably alters the lipid profile, approaching antilipemic drug efficacy.
9. Long-term effects of policosanol on obese patients with Type II Hypercholesterolemia
   It is concluded that policosanol was effective for lowering cholesterol in obese patients with type II hypercholesterolemia, being also safe and well tolerated.
10. Cholesterol-lowering action of policosanol compares well to that of pravastatin and lovastatin
    Cholesterol-lowering action of policosanol compares well to that of pravastatin and lovastatin
11. Effects of addition of policosanol to omega-3 fatty acid therapy on the lipid profile of patients with type II hypercholesterolaemia
    Policosanol 5 or 10 mg/day administered concomitantly with omega-3 FA 1 g/day improved LDL-C, TC and HDL-C, maintained the reduction in TG attributable to omega-3 FA monotherapy, and was well tolerated. Treatment with omega-3 FA + policosanol could be useful for regulating lipid profile in patients with type II hypercholesterolaemia, but further studies involving larger sample sizes are needed before definitive conclusions can be drawn.

1. Effect of a mediterranean type of diet on the rate of cardiovascular complications in patients with coronary artery disease insights into the cardioprotective effect of certain nutriments
   These data show a protective effect of the Mediterranean diet. However, the risk reduction varied depending on the type of end point considered. Our hypothesis is that different pathogenetic mechanisms were responsible for the development of the various complications. It is likely that certain nutriments characteristic of the Mediterranean diet (omega-3 fatty acids, oleic acid, antioxidant vitamins) have specific cardioprotective effects.
2. Mediterranean Diet, Traditional Risk Factors, and the Rate of Cardiovascular Complications After Myocardial Infarction
   The protective effect of the Mediterranean dietary pattern was maintained up to 4 years after the first infarction, confirming previous intermediate analyses. Major traditional risk factors, such as high blood cholesterol and blood pressure, were shown to be independent and joint predictors of recurrence, indicating that the Mediterranean dietary pattern did not alter, at least qualitatively, the usual relationships between major risk factors and recurrence. Thus, a comprehensive strategy to decrease cardiovascular morbidity and mortality should include primarily a cardioprotective diet. It should be associated with other (pharmacological?) means aimed at reducing modifiable risk factors. Further trials combining the 2 approaches are warranted.
3. Dietary Prevention of Coronary Heart Disease The Lyon Diet Heart Study
   This issue of Circulation contains an article1 that I believe deserves special attention from cardiologists and physicians. It reports the 46-month mean follow-up findings on the original report of the study on "Mediterranean a-linolenic acid–rich diet in secondary prevention of coronary heart disease," the so-called Lyon Diet Heart Study. This study was undertaken because of the interest of the investigators in explaining the very much lower mortality from cardiovascular disease, mainly coronary heart disease, in the countries bordering the Mediterranean compared with that in northern Europe. I suspect that we are just beginning to scratch the surface of the potential biological importance to health and disease of the n-3 class of essential PUFAs.
4. Mediterranean alpha-linolenic acid-rich diet in secondary prevention of coronary heart disease
   An alpha-linolenic acid-rich Mediterranean diet seems to be more efficient than presently used diets in the secondary prevention of coronary events and death.
5. Lyon Diet Heart Study Benefits of a Mediterranean-Style, National Cholesterol Education Program/American Heart Association Step I Dietary Pattern on Cardiovascular Disease
   Diet is a cornerstone of cardiovascular disease (CVD) prevention and treatment efforts. Step I and Step II diets are widely recommended as the first line of CVD intervention.1 At the core of this dietary guidance are the recommendations to decrease saturated fat and cholesterol and to consume more fruits, vegetables, and whole grain products. Information from an extensive database, especially regarding saturated fat, indicates that these diets significantly lower blood cholesterol levels, a major risk factor for CVD. Consequently, it is beyond debate that these diets reduce CVD risk. Since the advent of Step I and Step II diets, nutritionists have sought to develop effective implementation strategies, including identifying dietary patterns that augment the beneficial effects of these diets. Recent findings indicate that we are making impressive progress in attaining these goals. There is provocative evidence from the Lyon Diet Heart Study2 suggesting that a Mediterranean-style, Step I diet (emphasizing more bread, more root vegetables and green vegetables, more fish, less beef, lamb and pork replaced with poultry, no day without fruit, and butter and cream replaced with margarine high in a-linolenic acid) has effects that may be superior to those observed for the usual Step I diet. These findings raise the interesting, but not yet corroborated, question of whether a modified Step I diet (ie, a Mediterranean-style Step I diet) that features a dietary pattern consistent with the new American Heart Association (AHA) Dietary Guidelines may augment the Step I or Step II diets that are presently implemented in clinical practice.
6. Dietary fiber reduces peripheral arterial disease risk in men
   These results suggest an inverse association between cereal fiber intake and PAD risk in men. Increasing cereal fiber intake may prevent PAD.

1. Effect of garlic on cardiovascular disorders: a review
   Garlic and its preparations have been widely recognized as agents for prevention and treatment of cardiovascular and other metabolic diseases, atherosclerosis, hyperlipidemia, thrombosis, hypertension and diabetes. Effectiveness of garlic in cardiovascular diseases was more encouraging in experimental studies, which prompted several clinical trials. Though many clinical trials showed a positive effect of garlic on almost all cardiovascular conditions mentioned above, however a number of negative studies have recently cast doubt on the efficacy of garlic specially its cholesterol lowering effect of garlic. It is a great challenge for scientists all over the world to make a proper use of garlic and enjoy its maximum beneficial effect as it is the cheapest way to prevent cardiovascular disease. This review has attempted to make a bridge the gap between experimental and clinical study and to discuss the possible mechanisms of such therapeutic actions of garlic.
2. Effects of garlic on atherosclerosis
   This review discusses the use of garlic and garlic preparations as agents for prevention and treatment of atherosclerosis and atherosclerosis-related diseases. Garlic indirectly effects atherosclerosis by reduction of hyperlipidemia, hypertension, and probably diabetes mellitus and prevents thrombus formation. In addition, in animal models, garlic causes direct antiatherogenic (preventive) and antiatherosclerotic (causing regression) effects at the level of artery wall. Garlic's direct effect on atherosclerosis may be explained by its capacity to reduce lipid content in arterial cells and to prevent intracellular lipid accumulation. This effect, in turn, is accompanied by other atherosclerotic manifestations, i.e., stimulation of cell proliferation and extracellular matrix synthesis. Clinical trials are currently being carried out to reveal the possible effect of garlic therapy on human atherosclerosis. Positive results of these trials may open a new era in the use of garlic for prevention and treatment of many atherosclerosis-related diseases.
3. Historical Perspective on Garlic and Cardiovascular Disease
   Cardiovascular disease is a complex and multifactorial disease characterized by such factors as high cholesterol, hypertension, reduced fibrinolysis, increase in blood-clotting time and increased platelet aggregation. Dietary therapy is the first step in the treatment of hyperlipidemia; garlic has been used medicinally for centuries and is still included in the traditional medicine of many cultures. Historically, there has been great interest in the role of garlic in reducing cardiovascular risk factors. Evidence from numerous studies points to the fact that garlic can bring about the normalization of plasma lipids, enhancement of fibrinolytic activity, inhibition of platelet aggregation and reduction of blood pressure and glucose. However, some contradictory results have also emerged as a result of methodological shortcomings, the use of different formulations/preparations of garlic and different time scales of the studies. Accordingly, further clinical studies are required in which standardized formulations of garlic with known compositions can be used. Such formulations (e.g., Aged Garlic Extract) are now available and are being investigated. Evidence obtained from these studies indicates that garlic has potential in the prevention and control of cardiovascular disorders and is beneficial when taken as a dietary supplement.
4. Cardiovascular effects of garlic (Allium sativum): a review
   Garlic (Allium sativum) has been used medicinally for centuries and still is included in the traditional medicine of most cultures. Recently, there has been renewed interest in its role in the treatment of cardiovascular diseases and its effectiveness in offsetting the risks of such conditions. The results of numerous studies are reviewed; they show that garlic can bring about plasma lipids normalization, enhancement of fibrinolytic activity, inhibition of platelet aggregation, and reductions in blood pressure and blood glucose. It is concluded that garlic has potential in the prevention and control of cardiovascular disorders.
5. Garlic: its cardio-protective properties
   Evidence that garlic inhibits platelet aggregation, increases fibrinolysis, reduces blood pressure, enhances anti-oxidant activity, and reduces serum lipids suggests that it may have cardio-protective properties. The lack of qualitative standardization of garlic preparations and the methodological weaknesses of earlier studies makes comparison between different studies complicated. Quantitative pooling of data in meta-analyses of the primary trials strongly suggests that garlic is an effective lipid-lowering agent.
6. Effects of garlic on atherosclerosis
   This review discusses the use of garlic and garlic preparations as agents for prevention and treatment of atherosclerosis and atherosclerosis-related diseases. Garlic indirectly effects atherosclerosis by reduction of hyperlipidemia, hypertension, and probably diabetes mellitus and prevents thrombus formation. In addition, in animal models, garlic causes direct antiatherogenic (preventive) and antiatherosclerotic (causing regression) effects at the level of artery wall. Garlic's direct effect on atherosclerosis may be explained by its capacity to reduce lipid content in arterial cells and to prevent intracellular lipid accumulation. This effect, in turn, is accompanied by other atherosclerotic manifestations, i.e., stimulation of cell proliferation and extracellular matrix synthesis. Clinical trials are currently being carried out to reveal the possible effect of garlic therapy on human atherosclerosis. Positive results of these trials may open a new era in the use of garlic for prevention and treatment of many atherosclerosis-related diseases.
7. Review: cardiovascular effect of garlic (Allium sativum
   Garlic has been used for centuries, and even nowadays is part of popular medicine in many cultures. New data have increased the interest in garlic and its role in normalization and treatment of cardiovascular disease risk factors. Recent studies have shown the complex composition of garlic, containing many compounds, that present potential positive effect in the field of health. The aim of the present paper was to review results of some studies that have found a relationship between garlic and cardiovascular diseases. From some of them it can be summarized that garlic can normalize plasma lipid, check lipid peroxidation, stimulate fibrinolytic activity, inhibit platelet aggregation, smooth the thickening and structural changes of artery wall related to aging and atherosclerosis, and decrease blood pressure. However, some other studies do not support these benefits. The positive effects found have promoted many study projects, nevertheless, the extract lability and the lack of result consensus call for a moderate consumption of garlic and garlic extracts. The composition variation due to gathering and aging together with the changes occurring in canning and industrial treatment makes necessary the application of some norms in the production and consumption of this functional food in order to guarantee its use in adequate form and doses.

1. Olive oil and reduced need for antihypertensive medications
   A slight reduction in saturated fat intake, along with the use of extra-virgin olive oil, markedly lowers daily antihypertensive dosage requirement, possibly through enhanced nitric oxide levels stimulated by polyphenols.
2. Dietary olive oil reduces low-density lipoprotein uptake by macrophages and decreases the susceptibility of the lipoprotein to undergo lipid peroxidation
   We conclude that olive oil supplementation to the diet modifies LDL lipid composition and enriches the lipoprotein with oleic acid and sitosterol. The antiatherogenic properties of this modified lipoprotein may be related to its resistance to in vitro peroxidation and its reduced uptake by macrophages.
3. Dietary non-tocopherol antioxidants present in extra virgin olive oil increase the resistance of low density lipoproteins to oxidation in rabbits
   Results demonstrate that antioxidants, possibly phenolic compounds which are present only in extra virgin olive oil, may contribute to the endogenous antioxidant capacity of LDL, resulting in an increased resistance to oxidation as determined in vitro.

1. Omega-3 fatty acids in the prevention-management of cardiovascular disease
   Epidemiologic studies show that populations who eat fish versus those who do not have a reduced death rate from cardiovascular disease. Experimental studies have shown that omega-3 fatty acids affect the function of cells involved in atherothrombosis in numerous ways. The ingestion of omega-3 fatty acids following one episode of myocardial infarction appears to decrease the rate of cardiac death. These effects of omega-3 fatty acids appear to be due to their antiarrhythmic properties. In fact, fish oil has been shown to reduce ventricular arrhythmias and to be more beneficial than currently used pharmacologic agents. The dose, duration, and mechanisms involved in the prevention and management of cardiovascular disease following omega-3 fatty acid ingestion or supplementation need to be investigated by double blind controlled clinical trials.
2. Are fish oils beneficial in the prevention and treatment of coronary artery disease?
   The n-3 fatty acids of fish and fish oil have great potential for the prevention and treatment of patients with coronary artery disease. Especially important is the ability of these n-3 fatty acids to inhibit ventricular fibrillation and consequent cardiac arrest. Eicosapentaenoic acid has several antithrombotic actions, particularly in inhibiting the synthesis of thromboxane A2, the prostaglandin that causes platelet aggregation and vasoconstriction. Fish oil retards the growth of the atherosclerotic plaque by inhibiting both cellular growth factors and the migration of monocytes. Finally, fish oil has a mild blood pressure-lowering effect in both normal and mildly hypertensive individuals. These composite effects suggest a prominent therapeutic role for fish oil in the prevention and treatment of coronary artery disease.
3. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial
   Dietary supplementation with n-3 PUFA led to a clinically important and statistically significant benefit. Vitamin E had no benefit. Its effects on fatal cardiovascular events require further exploration.
4. The effect of dietary omega-3 fatty acids on coronary atherosclerosis. A randomized, double-blind, placebo-controlled trial
   Dietary intake of omega-3 fatty acids modestly mitigates the course of coronary atherosclerosis in humans.
5. Fish oil interaction with warfarin
   This case reveals a significant rise in INR after the dose of concomitant fish oil was doubled. Patients undergoing anticoagulation therapy with warfarin should be educated about and monitored for possible drug-herb interactions. Pharmacists can play a crucial role in identifying possible drug interactions by asking patients taking warfarin about herbal and other alternative medicine product use.
6. Effects of Marine Fish Oils on the Anticoagulation Status of Patients Receiving Chronic Warfarin Therapy
   One bruising episode was reported, yet no major bleeding episodes were observed during the study. Fish oil supplementation in doses of 3-6 grams per day does not seem to create a statistically significant effect on the anticoagulation status of patients receiving chronic warfarin therapy.
7. The importance of the ratio of omega-6/omega-3 essential fatty acids
   Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a low omega-6/omega-3 ratio) exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries, that are being exported to the rest of the world.
8. Interplay Between Different Polyunsaturated Fatty Acids and Risk of Coronary Heart Disease in Men
   n-3 PUFAs from both seafood and plant sources may reduce CHD risk, with little apparent influence from background n-6 PUFA intake. Plant-based n-3 PUFAs may particularly reduce CHD risk when seafood-based n-3 PUFA intake is low, which has implications for populations with low consumption or availability of fatty fish.
9. Dietary n-6 and n-3 fatty acid balance and cardiovascular health
   Based on published literature describing practical dietary intakes, we suggest that consumption of ~6% en LA, 0.75% en LNA, and 0.25% en EPA + DHA represents adequate and achievable intakes for most healthy adults. This corresponds to an n-6/n-3 ratio of ~6:1. However, the absolute mass of essential fatty acids consumed, rather than their n-6/n-3 ratio, should be the first consideration when contemplating lifelong dietary habits affecting cardiovascular benefit from their intake.
10. Effects of fish oil concentrate on lipoproteins and apolipoproteins in familial combined hyperlipidemia
    We conclude that in FCH moderate doses of long-chain n-3 fatty acids are highly effective in lowering pathological VLDL triglycerides, VLDL cholesterol, and VLDL apo B. LDL cholesterol must, however, be monitored during treatment as it may rise substantially in some although not in all patients with this disease.

1. Overview of the use of CoQ10 in cardiovascular disease
   The clinical experience in cardiology with CoQ10 includes studies on congestive heart failure, ischemic heart disease, hypertensive heart disease, diastolic dysfunction of the left ventricle, and reperfusion injury as it relates to coronary artery bypass graft surgery. The CoQ10-lowering effect of HMG-CoA reductase inhibitors and the potential adverse consequences are of growing concern. Supplemental CoQ10 alters the natural history of cardiovascular illnesses and has the potential for prevention of cardiovascular disease through the inhibition of LDL cholesterol oxidation and by the maintenance of optimal cellular and mitochondrial function throughout the ravages of time and internal and external stresses. The attainment of higher blood levels of CoQ10 (> 3.5 micrograms/ml) with the use of higher doses of CoQ10 appears to enhance both the magnitude and rate of clinical improvement. In this communication, 34 controlled trials and several open-label and long-term studies on the clinical effects of CoQ10 in cardiovascular diseases are reviewed.
2. Coenzyme Q10 therapy before cardiac surgery improves mitochondrial function and in vitro contractility of myocardial tissue
   Preoperative oral coenzyme Q(10) therapy in patients undergoing cardiac surgery increases myocardial and cardiac mitochondrial coenzyme Q(10) levels, improves mitochondrial efficiency, and increases myocardial tolerance to in vitro hypoxia-reoxygenation stress.
3. Protection by coenzyme Q10 from myocardial reperfusion injury during coronary artery bypass grafting
   Our findings suggest that pretreatment with coenzyme Q10 may play a protective role during routine bypass grafting by attenuating the degree of peroxidative damage..
4. Clinical experience of coenzyme Q10 to enhance intraoperative myocardial protection in coronary artery revascularization
   These results suggest that pretreatment with intravenous CoQ is effective in preventing left ventricular depression in early reperfusion and in minimizing myocardial cellular injury during CABG followed by reperfusion
5. Reperfusate composition: supplemental role of intravenous and intracoronary coenzyme Q10 in avoiding reperfusion d
   Intravenous coenzyme Q10, given just before reperfusion (possibly in transit to the operating room), enhances the role of substrate-enriched blood cardioplegic solution (especially when added to the cardioplegic solution) in salvaging ischemic myocardium and allowing immediate functional recovery.
6. Randomized, double-blind placebo-controlled trial of coenzyme Q10 in patients with acute myocardial infarction
   These findings suggest that coenzyme Q10 can provide rapid protective effects in patients with AMI if administered within 3 days of the onset of symptoms. More studies in a larger number of patients and long-term follow-up are needed to confirm our results.
7. Serum concentration of lipoprotein(a) decreases on treatment with hydrosoluble coenzyme Q10 in patients with coronary artery disease: discovery of a new role
   Supplementation with hydrosoluble coenzyme Q10 (Q-Gel) decreases lipoprotein(a) concentration in patients with acute coronary disease
8. Effect of coenzyme Q10 on risk of atherosclerosis in patients with recent myocardial infarction
   It is possible that treatment with CoQ10 in patients with recent MI may be beneficial in patients with high risk of atherothrombosis, despite optimal lipid lowering therapy during a follow-up of 1 year. Adverse effect of treatments showed that fatigue (40.8 vs. 6.8%, p < 0.01) was more common in the control group than CoQ group.
9. Response of patients in classes III and IV of cardiomyopathy to therapy in a blind and crossover trial with coenzyme Q10
   Coenzyme Q10 (CoQ10), a biochemically established redox component of respiration including the coupled mechanisms of electron transfer and oxidative phosphorylation, is naturally present in the human myocardium. A double-blind and double-crossover trial has been conducted by administering CoQ10 and a matching placebo orally to two groups of patients having class III or IV cardiomyopathy (classification according to criteria of the New York Heart Association). Group A received CoQ10 and then placebo; group B received placebo and then CoQ10. Blood levels of CoQ10 and cardiac function were determined at 0 and 4 weeks (control stabilization period) and at 16 and 28 weeks (after the 12-week CoQ/placebo-treatment periods). For group A, significant increases in CoQ10 blood levels and cardiac function occurred during CoQ10 treatment and then decreased during crossover to placebo. For group B, there was no change in CoQ10 blood levels and cardiac function during placebo treatment, but increases in both parameters occurred in crossover to CoQ10. These patients, steadily worsening and expected to die within 2 years under conventional therapy, generally showed an extraordinary clinical improvement, indicating that CoQ10 therapy might extend the lives of such patients. This improvement could be due to correction of a myocardial deficiency of CoQ10 and to enhanced synthesis of CoQ10-requiring enzymes.
10. Therapy with coenzyme Q10 of patients in heart failure who are eligible or ineligible for a transplant
    Twenty years of international open and seven double blind trials established the efficacy and safety of coenzyme Q10 (CoQ10) to treat patients in heart failure. In the U.S., ca. 20,000 patients under 65 years are eligible for transplants, but donors are less than 1/10th of those eligible, and there are many more such patients over 65, both eligible and ineligible. We treated eleven exemplary transplant candidates with CoQ10; all improved; three improved from Class IV to Class I; four improved from Classes III-IV to Class II; and two improved from Class III to Class I or II. After CoQ10, some patients required no conventional drugs and had no limitation in lifestyle. The marked improvement is based upon correcting myocardial deficiencies of CoQ10 which improve mitochondrial bioenergetics and cardiac performance. These case histories, and very substantial background proof of efficacy and safety, justify treating with CoQ10 patients in failure awaiting transplantation.
11. Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors
    Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.

1. Effects of L-carnitine administration on left ventricular remodeling after acute anterior myocardial infarction: the L-Carnitine Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) Trial
   L-Carnitine treatment initiated early after acute myocardial infarction and continued for 12 months can attenuate left ventricular dilation during the first year after an acute myocardial infarction, resulting in smaller left ventricular volumes at 3, 6 and 12 months after the emergent event.
2. Myocardial infarction and left ventricular remodeling: results of the CEDIM trial. Carnitine Ecocardiografia Digitalizzata Infarto Miocardico
   Ecocardiografia Digitalizzata Infarto Miocardico (CEDIM) trial suggest that the early and long-term administration of L-carnitine attenuates progressive left ventricular dilatation after acute anterior MI. Results show significant, consistent reductions in end-diastolic volume and end-systolic volume in patients who received L-carnitine compared with placebo.
3. Prolonged oral L-carnitine substitution increases bicycle ergometer performance in patients with severe, ischemically induced cardiac insufficiency
   The findings presented in this paper support suggestions of other authors that L-carnitine in combination with the usual medication (digitalis, beta-blockers, calcium antagonists, nitrates) improves performance and effort tolerance in patients with cardiac insufficiency. Moreover, the findings suggest a favourable long-term effect, which lasts beyond the actual L-carnitine application, on the performance of patients with advanced cardiac insufficiency.
4. Effects of L-carnitine on exercise tolerance in chronic stable angina: a multicenter, double-blind, randomized, placebo controlled crossover study
   The results of this study show that treatment with L-carnitine increases exercise tolerance and reduces ECG indices of ischemia in stable effort-induced angina.
5. A randomised, double-blind, placebo-controlled trial of L-carnitine in suspected acute myocardial infarction
   It is possible that L-carnitine supplementation in patients with suspected acute myocardial infarction may be protective against cardiac necrosis and complications during the first 28 days.
6. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study
   A double-blind, cross-over study was designed to evaluate the effects of L-carnitine in patients with peripheral vascular disease. After drug washout, 20 patients were randomly assigned to receive placebo or L- carnitine (2 g bid, orally) for a period of 3 weeks and were then crossed over to the other treatment for an additional 3 weeks. The effect on walking distance at the end of each treatment period was measured by treadmill test. Absolute walking distance rose from 174 +/- 63 m with placebo to 306 +/- 122 m (p less than .01) with carnitine. Biopsy of the ischemic muscle, carried out before and after 15 days of L-carnitine administration in four additional patients, showed that treatment significantly increased total carnitine levels. An additional goal of this study was to ascertain the effects of L-carnitine on the metabolic changes induced by exercise in the affected limb. In six patients under control conditions, arterial and popliteal venous lactate and pyruvate concentrations were determined at rest, when the maximal walking distance was reached, and 5 min after the walking test. Twenty-four hours later, L-carnitine was administered intravenously (3 g as a bolus followed by an infusion of 2 mg/kg/min for 30 min) and metabolic assessments were repeated. Five minutes after the walking test, popliteal venous lactate concentration increased by 107 +/- 16% before treatment and by only 54 +/- 32% (p less than .01) after carnitine. Furthermore, carnitine induced a more rapid recovery to the resting value of the lactate/pyruvate ratio
7. Therapeutic Effects of l-Carnitine and Propionyl-l-carnitine on Cardiovascular Diseases: A Review
   The results of phase-2 studies in chronic heart failure patients showed that long-term oral treatment with propionyl-l-carnitine improves maximum exercise duration and maximum oxygen consumption over placebo and indicated a specific propionyl-l-carnitine effect on peripheral muscle metabolism. A multicenter trial on 537 patients showed that propionyl-l-carnitine improves exercise capacity in patients with heart failure, but preserved cardiac function.
8. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and L-carnitine administration
   L-carnitine appears to possess considerable potential for the long-term treatment of patients with heart failure attributable to dilated cardiom

1. Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria
   Betaine plasma concentrations change rapidly after ingestion. Elimination half-life increased during continuous dosing over 5 days. Betaine is mainly eliminated by metabolism. More pharmacokinetic and pharmacodynamic studies in hyperhomocysteinaemic patients are needed to refine the current treatment with betaine.
2. Effects of betaine intake on plasma homocysteine concentrations and consequences for health
   Folic acid lowers plasma homocysteine by 25% maximally, because 5-methyltetrahydrofolate is a methyl donor in the remethylation of homocysteine to methionine. Betaine (trimethylglycine) is also a methyl donor in homocysteine remethylation, but effects on homocysteine have been less thoroughly investigated. Studies in healthy volunteers with plasma homocysteine concentrations in the normal range show that betaine supplementation lowers plasma fasting homocysteine dose-dependently to up to 20% for a dose of 6 g/d of betaine. Moreover, betaine acutely reduces the increase in homocysteine after methionine loading by up to 50%, whereas folic acid has no effect. This implies that betaine can be an important food component that attenuates homocysteine rises after meals. However betaine and choline may adversely affect serum lipid concentrations, which can of course increase risk of cardiovascular disease.
3. Methylation demand: a key determinant of homocysteine metabolism
   Homocysteine is removed either by its irreversible conversion to cysteine (transsulfuration) or by remethylation to methionine. There are two separate remethylation reactions, catalyzed by betaine:homocysteine methyltransferase and methionine synthase, respectively.
4. Effect of homocysteine-lowering nutrients on blood lipids: results from four randomised, placebo-controlled studies in healthy humans
   Betaine supplementation increased blood LDL cholesterol and triacylglycerol concentrations in healthy humans, which agrees with the limited previous data. The adverse effects on blood lipids may undo the potential benefits for cardiovascular health of betaine supplementation through homocysteine lowering.
5. Low dose betaine supplementation leads to immediate and long term lowering of plasma homocysteine in healthy men and women
   Thus, doses of betaine in the range of dietary intake reduce fasting and postmethionine loading plasma homocysteine concentrations. A betaine-rich diet might therefore lower cardiovascular disease risk.

1. Effect of niacin on atherosclerotic cardiovascular disease
   Thus, the use of niacin to prevent or treat atherosclerotic cardiovascular disease is based on strong and consistent evidence from clinical trials.

1. Tea flavonoids may protect against atherosclerosis: the Rotterdam Study
   This study indicates a protective effect of tea drinking against ischemic heart disease
2. Inverse association of tea and flavonoid intakes with incident myocardial infarction: the Rotterdam Study
   An increased intake of tea and flavonoids may contribute to the primary prevention of ischemic heart disease.
3. Relation between green tea consumption and the severity of coronary atherosclerosis among Japanese men and women
   The results indicate that green tea may be protective against coronary atherosclerosis at least in men
4. The role of tea and tea flavonoids in cardiovascular health
   Consumption of green or black tea has been inversely associated with the development and progression of cardiovascular diseases. Overall, tea represents a promising tool for the prevention and treatment of cardiovascular disorders.
5. The green tea, a good choice for cardiovascular disease prevention?
   The positive effects found suggest that a daily intake of 7 cups of green tea (3.5 g catechins) is a good choose for CHD prevention; however, it is still necessary more studies to check the action of the green tea and its catechins in humans in order to recommended its use in the general population or only in target subjects.
6. Tea flavonoids and cardiovascular health
   Tea is rich in antioxidant polyphenols (catechins, flavonols, theaflavins and thearubigins). Epidemiological evidence relating regular consumption of tea or related polyphenols to CHD is equivocal. The plasma antioxidant potential increases after drinking green but not black tea.
7. Short- and Long-Term Black Tea Consumption Reverses Endothelial Dysfunction in Patients With Coronary Artery Disease
   Short- and long-term black tea consumption reverses endothelial vasomotor dysfunction in patients with coronary artery disease. This finding may partly explain the association between tea intake and decreased cardiovascular disease events.
8. Green tea (Camellia sinensis) extract and its possible role in the prevention of cancer
   Current studies are hopeful, as they show an inverse association between green tea consumption and cancer risk, supporting a possible chemopreventive effect of green tea. Based on the knowledge that green tea is inexpensive, non-toxic, and is a popular beverage consumed worldwide, clinical trials should be conducted to evaluate the in-vivo effectiveness of green tea polyphenols on the inhibition and chemopreventive treatment of cancer.
9. Polyphenols and cardiovascular disease: effects on endothelial and platelet function
   Epidemiologic studies suggest that higher polyphenol intake from fruits and vegetables is associated with decreased risk for cardiovascular disease. The mechanisms explaining this observation remain unclear. This review summarizes data suggesting that flavonoids improve endothelial function and inhibit platelet aggregation in humans. The vascular endothelium is a critical regulator of vascular homeostasis, and endothelial dysfunction contributes to the pathogenesis and clinical expression of coronary artery disease. Platelet aggregation is a central mechanism in the pathogenesis of acute coronary syndromes, including myocardial infarction and unstable angina. For these reasons, the observed effects of flavonoids on endothelial and platelet function might explain, in part, the observed beneficial effects of flavonoids on cardiovascular disease risk.
10. The effects of green tea ingestion over four weeks on atherosclerotic markers
    The results of this study suggest an in vivo anti-oxidative effect for green tea and an influence of green tea on atherosclerotic biological markers. The effect of green tea seen on ox-LDL and sVCAM-1 provides a potential mechanism for the cardiovascular benefits of regular ingestion of green tea.

1. Ginkgo biloba special extract EGb 761 in the treatment of peripheral arterial occlusive disease (PAOD)--a review based on randomized, controlled studies
   This review confirms the efficacy of Ginkgo biloba special extract EGb 761. It demonstrates not only the statistical significance of the difference with respect to placebo but also the clinical relevance for the treatment of patients with PAOD.
2. Placebo-controlled double-blind study of the effectiveness of Ginkgo biloba special extract EGb 761 in trained patients with intermittent claudication
   The results of this placebo-controlled study show that treatment with Ginkgo biloba special extract EGb 761 produces a statistically highly significant and clinically relevant improvement of the walking performance in trained patients suffering from intermittent claudication with very good tolerance of the study preparation.
3. Comparison of two dosages of ginkgo biloba extract EGb 761 in patients with peripheral arterial occlusive disease Fontaine's stage IIb. A randomised, double-blind, multicentric clinical trial
   Both dosage regimens investigated in this trial led to a clinically relevant improvement of the pain-free walking distance after 24 weeks of treatment. The superiority of the higher dosage over the standard dosage was statistically significant. Both treatment variations were safe and well tolerated.
4. 6-Month double-blind randomised clinical trial of Ginkgo biloba extract versus placebo in two parallel groups in patients suffering from peripheral arterial insufficiency
   79 patients suffering from peripheral arteriopathy (Fontaine's stage IIb) completed a 6-month double-blind randomised clinical trial of Ginkgo biloba extract (GBE) (as coated tablets containing 40 mg GBE; rokan) versus placebo in two parallel groups. From the results of measurements of pain-free walking distance, maximum walking distance and plethysmography recordings, GBE was shown to be active and significantly superior to placebo. These results correlated with the physician's and patients' overall assessment of response to treatment.
5. Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication--a placebo-controlled, double-blind multicenter trial
   It can be concluded from the results of this study that treatment with EGb 761 in POAD patients with Fontaine stage II b is very safe and causes a significant and therapeutically relevant prolongation of the patients' walking distance.
6. Efficacy and safety of a Ginkgo biloba extract
   This review of the literature documents the efficacy of a standard extract of Ginkgo biloba (EGb) in managing signs and symptoms associated with memory disorders and dementia. Analysis of the discrepant findings reveals that study outcomes may vary with the type of population studied, the outcome measurements selected, and the dosing tested. Overall, the efficacy of EGb was more frequently reported in trials enrolling dementia patients than healthy volunteers. In contrast to narrow memory tests, broad cognitive assessments were more likely to detect the treatment effect. Although a dose--response relationship is not yet established, 240 mg day(-1) EGb seems to show a higher rate of treatment response than does 120 mg day(-1). Regarding safety, in all trials reviewed the adverse event profile of EGb was not different from that of the placebo.
7. Ginkgo biloba extract in peripheral arterial diseases. Meta-analysis of controlled clinical studies
   In the first part the statistical methods of meta-analysis are discussed. Meta-analysis is considered as a statistical tool for quantitatively summarizing the results of clinical trials with comparable aims (treatments) and designs. Meta-analysis can be based on the significance probabilities or effect values. The last procedure is preferable as it gives an estimate (and confidence interval) for the global effect of the treatment of interest, if homogeneity of the effects between the trials can be assumed. Such a homogeneity can be often achieved by a suitable standardization of the effect variables within the trials. In the second part the methods of meta-analysis are applied to controlled clinical trials with Ginkgo biloba extract EGb 761 in patients with peripheral arterial disease. Included were 5 placebo-controlled clinical trials with similar design and inclusion criteria. In all studies treatment effect was quantified by the increase of walking distance (measured in standardized treadmill exercise). The effect value of EGb 761 treatment was expressed by the standardized mean difference in walking distance increase between EGb 761 and placebo, standardized by the standard deviation. It could be shown that this effect value is homogeneous in all trials. The global effect size was estimated as 0.75. This means that the mean increase in walking distance achieved by EGb 761 is 0.75 times of the standard deviation higher than that achieved by placebo. This value is highly significant different from zero. So the meta-analysis revealed a highly significant therapeutic effect of EGb 761 for the treatment of peripheral arterial disease.

1. L-arginine therapy in acute myocardial infarction: the Vascular Interaction With Age in Myocardial Infarction (VINTAGE MI) randomized clinical trial
   L-arginine, when added to standard postinfarction therapies, does not improve vascular stiffness measurements or ejection fraction and may be associated with higher postinfarction mortality. L-arginine should not be recommended following acute myocardial infarction.Clinical Trial Registration
2. Angina with "normal" coronary arteries: a changing philosophy
   Randomized placebo-controlled studies have demonstrated that tricyclic antidepressants, beta-blockers, angiotensin-converting enzyme inhibitors, L-arginine, statins, and exercise may relieve symptoms,
3. Oral L-arginine improves endothelium-dependent dilatation and reduces monocyte adhesion to endothelial cells in young men with coronary artery disease
   In young men with coronary artery disease, oral L-arginine improves endothelium-dependent dilatation and reduces monocyte/endothelial cell adhesion.
4. Oral L-arginine improves endothelial function in healthy individuals older than 70 years
   We conclude that in healthy very old age endothelial function is impaired and may be improved by oral L-arginine supplementation, probably due to normalization of the L-arginine/ADMA ratio
5. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia: effects of L-arginine and B vitamins
   Oral supplementation with combined B vitamins during 8 weeks does not improve endothelium-dependent vasodilation in PAOD patients with hyperhomocyst(e)inemia, whereas L-arginine significantly improved endothelial function in these patients. Thus, accumulation of ADMA and increased oxidative stress may underlie endothelial dysfunction under hyperhomocyst(e)inemic conditions. These findings may have importance for evaluation of homocyst(e)ine-lowering therapy.
6. Oral L-arginine improves endothelial dysfunction in patients with essential hypertension
   Oral administration of L-arginine acutely improves endothelium-dependent, flow-mediated dilatation of the brachial artery in patients with essential hypertension. The long-term effects of L-arginine in these patients require further investigation.
7. Long-term L-arginine supplementation improves small-vessel coronary endothelial function in humans
   Long-term oral L-arginine supplementation for 6 months in humans improves coronary small-vessel endothelial function in association with a significant improvement in symptoms and a decrease in plasma endothelin concentrations. This study proposes a role for L-arginine as a therapeutic option for patients with coronary endothelial dysfunction and nonobstructive coronary artery disease.

1. Red yeast rice: a new hypolipidemic drug
   Red yeast rice is a source of fermented pigment with possible bioactive effect. Evidence shows that fermented red yeast rice lowers cholesterol levels moderately compared to other statin drugs, but with the added advantage of underscores its potential as a new alternative to lipid level control. It is concluded from the present evidence that other types of pigmented rice possess opportunities for development as new functional foods.
2. Cardiovascular disease: C-reactive protein and the inflammatory disease paradigm: HMG-CoA reductase inhibitors, alpha-tocopherol, red yeast rice, and olive oil polyphenols. A review of the literature
   The current understanding of the origin of atherosclerosis is that of an inflammatory process that involves the acute phase response -an innate biological response to a disturbance in homeostasis -infection, inflammation, tissue injury, neoplasm, or immune disturbance. The activation of the acute phase response, signaled by interleukin-6, produces proteins (fibrinogen, C-reactive protein (CRP), serum amyloid A) that lead to inflammatory reactions. The tissues themselves contain elevated levels of acute phase proteins and cytokines resulting in a localized inflammatory effect. Localized inflammatory responses in the intimal layer of the arterial wall have been shown to be responsible for many of the aspects of intimal thickening and plaque disruption, leading to acute cardiovascular events. The predictive value of plasma C-reactive protein as a risk factor for cardiovascular events has led some researchers to support the use of CRP as a main cardiovascular risk assessment tool, along with total cholesterol:HDL ratios and homocysteine levels. The ability of HMG-CoA reductase inhibitors to lower C-reactive protein levels has recently brought into question the mechanisms of action of the statin drugs. Because these medications lower incidences of acute cardiovascular events as well as decreasing morbidity and mortality well before the effects of lowered LDL cholesterol can be expected to occur, questions have been asked about whether they may work independently of LDL-lowering mechanisms. Red yeast rice contains a naturally-occurring statin (lovastatin) as well as other cholesterol-lowering compounds, some with antioxidant effects. Alpha-tocopherol also significantly lowers CRP levels in diabetics and nondiabetics, and minimizes other aspects of the acute phase response and inflammatory damage involved in atherosclerosis. This may account for alpha-tocopherol's positive effect on cardiovascular morbidity and mortality. Finally, polyphenolic compounds present in virgin olive oil also have anti-inflammatory and antioxidative effects in cardiovascular disease. The phenolic compounds in virgin olive oil may explain some of the protective effects found in epidemiological studies.
3. Plasma clearance of lovastatin versus chinese red yeast rice in healthy volunteers
   The results suggested that the effect of CRYR on the cholesterol concentration might be caused by the additive and/or synergistic effects of monacolin K with other monacolins and substances in CRYR. It may lead to the ultimate development of a botanical supplement based on CRYR.
4. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement
   Red yeast rice significantly reduces total cholesterol, LDL cholesterol, and total triacylglycerol concentrations compared with placebo and provides a new, novel, food-based approach to lowering cholesterol in the general population.
5. An analysis of nine proprietary Chinese red yeast rice dietary supplements: implications of variability in chemical profile and contents
   The findings from clinical trials demonstrating significant and clinically relevant cholesterol reduction using a defined Chinese red yeast rice preparation containing 10 different monacolins cannot be generalized to preparations that do not contain the same levels and profile of monacolins. Standardized manufacturing practices should be established for Chinese red yeast rice sold as a dietary supplement in order ensure equivalence of content of active ingredients in preparations being sold to the public and to limit the production of unwanted byproducts of fermentation such as citrinin. In common with other botanical dietary supplements, the full potential of this product will not be realized until standards for production and labeling of Chinese red yeast rice are further developed.
6. Antiatherosclerotic efficacy of policosanol, red yeast rice extract and astaxanthin in the rabbit
   The results support the rationale of a combination of P, RYE and A as a useful food supplement in hyperlipemic patients
7. Acute administration of red yeast rice (Monascus purpureus) depletes tissue coenzyme Q(10) levels in ICR mice
   In conclusion, acute red yeast rice gavage suppressed hepatic and cardiac CoQ10 levels in rodents; furthermore, the inhibitory effect was responsive to the doses administered.

1. Lipoprotein lipase and atherosclerosis
   Lipoprotein lipase (LPL) is a rate-limiting enzyme that hydrolyzes circulating triglyceride-rich lipoprotein such as very low density lipoproteins and chylomicrons. A decrease in LPL activity is associated with an increase in plasma triglycerides (TG) and decrease in high density lipoprotein (HDL) cholesterol. However, whether LPL directly or indirectly promotes or protects against atherosclerosis remains unclear as two contrary views exist in this regard: one where LPL promotes atherosclerosis and one where LPL protects against atherosclerosis. Many studies have been carried out to investigate whether LPL is an anti-atherogenic or atherogenic enzyme by using animals with genetic defects or with an excess of this enzyme. From these studies, much evidence has been acquired showing that LPL is an anti-atherogenic enzyme. We hypothesized that elevating LPL activity would cause a reduction of plasma TG and increase in HDL cholesterol, resulting in protection against the development of atherosclerosis. The results of multiple regression analysis in these studies suggest that the increase in plasma HDL cholesterol and the decrease in TG protect against atherosclerosis. We have determined in our studies that the atherogenic lipid profile is changed to an anti-atherogenic lipid profile by increasing LPL activity, resulting in protection against the development of atherosclerosis. Therefore, we believe that high activity of LPL is anti-atherogenic, whereas a low activity of LPL is atherogenic.
2. Lipoprotein lipase and atherosclerosis
   Lipoprotein lipase (LPL) is a key enzyme in catabolism of plasma lipoprotein triglycerides (TGs), and in that capacity has a salutary influence on plasma HDL, and thus appears to be antiatherogenic. However, the non-catalytic functions of LPL, such as lipoprotein bridging and selective uptake of lipoprotein cholesteryl ester, are regarded as proatherogenic. The balance between the pro and antiatherogenic attributes of LPL is evaluated on the basis of recent evidence derived from transgenic animals and from studies of common LPL mutations in man. This review also includes recently accrued information on the role of nuclear receptors and their ligands and agonists in regulation of LPL in various organs. The studies reviewed are not only of academic interest, but may also have practical applications in development of agents that may regulate LPL activity in humans.
3. Lipoprotein lipase-mediated myopathy: implications for lipid metabolism and atherogenesis
   It is suggested, that LPL derived from endothelial cells and macrophages--besides other atherogenic mechanisms--can mediate cholesterol ester influx into the vessel wall and thereby promote proatherogenic modifications. Although due to its hydrolytic function, LPL is generally considered an antiatherogenic enzyme, endothelial LPL can locally facilitate atherogenesis.
4. Lipoprotein lipase (LPL) in the pathogenesis of atherosclerosis
   The role of lipoprotein lipase (LPL) in the development of atheromatosis is subject of the increased interest for about 20 years, since then Zilversmit observed that LPL activity is found in greater amounts in atherosclerotic than normal arteries. The general action of this enzyme is hydrolysis of triglycerides in triglyceride rich lipoproteins and thus regulation of metabolism of circulating as well antiatherogenic as proatherogenic lipoproteins. The effect of LPL on the biology of arterial wall seems to be atherogenic. The mechanisms of this effect of LPL is 1) augmentation of the adhesion and aggregation of LDL; 2) influence on the oxygen modification of LDL and increased uptake of oxy-LDL by macrophages; 3) dysfunction of endothelial barrier and retention of atherogenic lipoproteins in the arterial wall and 4) the activity of LPL macrophage origin. Possible atherogenic actions of LPL based on in vitro experimental studies are reviewed.
5. Role of hepatic and lipoprotein lipase in lipoprotein metabolism and atherosclerosis: studies in transgenic and knockout animal models and somatic gene transfer
   Hepatic lipase (HL) and lipoprotein lipase (LPL) are the two major lipolytic enzymes responsible for the hydrolysis of triglycerides and phospholipids present in circulating plasma lipoproteins. Both lipases are attached to the vascular endothelium via cell surface proteoglycans. HL is primarily involved in the metabolism of chylomicron remnants, intermediate density lipoproteins and high-density lipoproteins whereas LPL catalyzes the hydrolysis of triglycerides from chylomicrons and very low-density lipoproteins.

1. Evolution and progression of atherosclerotic lesions in coronary arteries of children and young adults
   In an autopsy study of the evolution of atherosclerotic lesions in young people, we obtained the coronary arteries and aortas of 1160 male and female subjects who died between full-term birth and age 29 years. In this article, we report the light and electron microscopic observations of the coronary arteries of 565 of these subjects in which we fixed the coronary arteries by perfusion with glutaraldehyde under pressure. From birth, the intima was always thicker in the half of the coronary artery circumference opposite the flow-divider wall of a bifurcation (eccentric thickening). In cases where we found lipid in the intima, there was always more in eccentric thickening. Isolated macrophage foam cells in the intima of infants were the earliest sign of lipid retention. These cells occurred in 45% of infants in the first 8 months of life but decreased subsequently. At puberty, more substantial accumulations of macrophage foam cells reappeared in more children. Foam cells were now accompanied by lipid droplets in existing smooth muscle cells and by thinly scattered extracellular lipid. Sixty-five percent of children between ages 12 and 14 years had such lesions. An additional 8% of children had progressed beyond this early stage and had developed advanced preatheroma or atheroma stages. Such advanced lesions, located only in areas of eccentric thickening, were characterized by the addition of massive extracellular lipid that displaced normal cells and matrix and, thus, damaged and weakened the arterial wall.
2. Dietary flavonoids, antioxidant vitamins, and incidence of stroke: the Zutphen study
   Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). The habitual intake of flavonoids and their major source (tea) may protect against stroke.
3. Dietary Macrophages, macrophage foam cells, and eccentric intimal thickening in the coronary arteries of young children
   We surveyed the incidence and location of macrophages and macrophage foam cells in the coronary artery intima of 63 children that died in the first 5 years of life. We related the data on macrophages and macrophage foam cells to intimal smooth muscle cells and to measurements of intima:media area and thickness.

1. Dose optimization of intravenous magnesium sulfate after acute stroke
   MgSO4 infusions that rapidly elevate the serum magnesium concentration to potentially therapeutic levels are well tolerated and have no major hemodynamic effects in patients with acute stroke. The 16-mmol loading infusion achieved target serum concentrations most rapidly and has been chosen for further trials.
2. The safety and feasibility of continuous intravenous magnesium sulfate for prevention of cerebral vasospasm in aneurysmal subarachnoid hemorrhage
   Cerebral vasospasm in aneurysmal subarachnoid hemorrhage (SAH) is associated with poor outcome. The safety and feasibility of continuous high-dose intravenous magnesium sulfate (MgSO4) for the prevention of cerebral vasospasm and ischemic cerebral injury has not been well studied. Our study confirmed the safety and feasibility of a continuous infusion of high-dose intravenous MgSO4 in patients with aneurysmal SAH. Randomized controlled trials are required to confirm the promising results.
3. Intravenous administration of magnesium sulfate in acute stroke: a randomized double-blind study
   Intravenous magnesium sulfate had significant positive effect on the outcome in patients with acute stroke. Further studies on a larger scale are needed to confirm these findings.
4. Magnesium as a neuroprotectant in cardiac surgery: a randomized clinical trial
   Magnesium administration is safe and improves short-term postoperative neurologic function after cardiac surgery, particularly in preserving short-term memory and cortical control over brainstem functions. However, by 3 months, other factors and not administration of magnesium influence neuropsychologic and depression inventory performance.
5. A Randomized, Double-Blind, Placebo-Controlled Pilot Trial of Intravenous Magnesium Sulfate in Acute Stroke
   Magnesium ions act as endogenous vasodilators of the cerebral circulation and act pharmacologically as noncompetitive antagonists of the N-methyl-D-aspartate receptor by virtue of their role as endogenous voltage-sensitive blockers of the ion channel. The preclinical efficacy of magnesium has been demonstrated in standard models of stroke.

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