Hyperhomocysteinaemia, defined as an abnormally high plasma homocysteine concentration after an oral methionine load, is common in young (< or = 50 years) patients with peripheral arterial occlusive disease. It is thought to predispose to atherosclerosis by injuring the vascular endothelium. Treatment with pyridoxine and/or folic acid may lower plasma homocysteine levels. In mildly hyperhomocysteinaemic patients with peripheral arterial occlusive disease, we studied the effect of daily treatment with pyridoxine (250 mg) plus folic acid (5 mg) on homocysteine metabolism (i.e. plasma concentrations in the fasting state and after methionine loading, in 48 patients) and on endothelial function (in 18 patients). Endothelial function was estimated as the plasma concentrations of the endothelium-derived proteins, von Willebrand factor (vWF), thrombomodulin (TM), and tissue-type plasminogen activator (tPA). At baseline, fasting homocysteine levels were above normal in 24 of the 48 patients (50%); post-load levels, by definition, were above normal in 100% of patients. After 12 weeks of treatment, fasting and post-load levels were normal in 98 and 100% of patients, respectively. Endothelial function was assessed in 18 patients who completed 1 year of treatment. At baseline, median vWF (235%) and TM (57.1 ng mL-1) levels were above normal. At follow-up, vWF levels had decreased to 170% (P = 0.01) and TM levels had decreased to 49 ng mL-1 (P = 0.04). tPA levels were normal at baseline and did not change. Endothelial dysfunction is present in young patients with peripheral arterial occlusive disease and hyperhomocysteinaemia. Pyridoxine plus folic acid treatment normalizes homocysteine metabolism in virtually all patients, and appears to ameliorate endothelial dysfunction.

/pdf/hyperhomocysteinaemia-and-endothelial-dysfunction-in-young-2fbirme66y.pdf

Hyperhomocysteinaemia and endothelial dysfunction in young patients with peripheral arterial occlusive disease.

During progression of atherosclerosis the overlying endothelial cells alter their expression of some surface molecules. Circulating levels of such molecules may be quantified. We investigated the effect of omega-3 fatty acids (n-3 FA) on the levels of tissue plasminogen activator antigen, von Willebrand factor, and the soluble forms of thrombomodulin, P-selectin, E-selectin, and vascular cell adhesion molecule-1 in 54 patients with coronary heart disease. Twenty-three of the patients had taken 5.1 g/d n-3 FA for 6 months (group I) and 31 were given corn oil as placebo (group II). For another 4 weeks ("the study period") they all got 5.1 g/d of n-3 FA. Compliance was confirmed by demonstration of changes in relevant fatty acids in serum phospholipids. At baseline, significant differences between the groups were found with lower median values of von Willebrand factor (128% versus 147%) and soluble thrombomodulin (24.9 versus 32.5 ng/mL) and higher median values of soluble E-selectin (41.4 versus 35.5 ng/mL) and soluble vascular cell adhesion molecule-1 (573 versus 473 ng/mL) in group I. During the study period differences in changes between the groups were found; tissue plasminogen activator antigen and soluble thrombomodulin decreased (P for difference between the groups 0.001 and 0.015, respectively), whereas soluble E-selectin and soluble vascular cell adhesion molecule-1 increased (P for difference between the groups <0.01 for both) in group II relative to group I. Our results indicate that n-3 FA supplementation decreases hemostatic markers of atherosclerosis, whereas markers of inflammation may be increased. The latter may be the result of lipid peroxidation as a simultaneous decrease of vitamin E and increase in thiobarbituric acid-reactive substances were observed.

The Effect of Supplementation With Omega-3 Fatty Acids on Soluble Markers of Endothelial Function in Patients With Coronary Heart Disease

Mildly elevated plasma homocysteine levels are an independent risk factor for atherothrombotic vascular disease in the coronary, cerebrovascular, and peripheral arterial circulation. Endothelial dysfunction as manifested by impaired endothelium-dependent regulation of vascular tone and blood flow, by increased recruitment and adhesion of circulating inflammatory cells to the endothelium, and by a loss of endothelial cell antithrombotic function contributes to the vascular disorders linked to hyperhomocysteinemia. Increased vascular oxidant stress through imbalanced thiol redox status and inhibition of important antioxidant enzymes by homocysteine results in decreased bioavailability of the endothelium-derived signaling molecule nitric oxide via oxidative inactivation. This plays a central role in the molecular mechanisms underlying the effects of homocysteine on endothelial function. Supplementation of folic acid and vitamin B12 has been demonstrated to be efficient in lowering mildly elevated plasma homocysteine levels and in reversing homocysteine-induced impairment of endothelium-dependent vasoreactivity. Results from ongoing intervention trials will determine whether homocysteine-lowering therapies contribute to the prevention and reduction of atherothrombotic vascular disease and may thereby provide support for the causal relationship between hyperhomocysteinemia and atherothrombosis.

https://journals.sagepub.com/doi/pdf/10.1191/1358863x02vm428ra

Endothelial dysfunction and atherothrombosis in mild hyperhomocysteinemia

Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease

More than 150 years ago, Virchow proposed that abnormalities in blood flow, vessel wall and blood components predispose to thrombosis, constituting what is now known as ‘Virchow's triad’ for thrombogenesis.1 This rather simplistic view has been continually modified by new discoveries and concepts, as we now know that the process of thrombus formation requires complex interactions involving injury to the vascular endothelium, platelet adherence, aggregation and release, and clotting factor activation, eventually leading to thrombin generation and fibrin formation.2

The endothelium has many vital and diverse (depending on the particular vascular bed) physiological roles, such as regulation of blood vessel tone, permeability, metabolism and haemostasis. Impairment of endothelial function manifests clinically as oedema, hypertension, abnormal vasoconstriction and hypercoagulability. Indeed, it is a widely held view that impaired endothelial function is also the initial step in atherogenesis, which is largely responsible for ischaemic heart disease and thrombotic strokes decades later. Impaired endothelial function is also associated with hypertension, diabetes mellitus and heart failure (regardless of aetiology), although whether as a cause or a consequence is undetermined. Hence, understanding endothelial function is likely to be a key to modifying risk factors of cardiovascular disorders and their sequelae.

Nevertheless, the ideal method(s) of assessing endothelial physiology (and, therefore, pathology) remains uncertain. Various indices have been used to assess endothelial activation, dysfunction and damage: the ideal index would not only be specific to the endothelium but would also be stable and easily measurable—the ‘gold standard’ remains uncertain, as available indices quantify different aspects of endothelial physiology. In addition, words such as damage, injury, dysfunction and activation are currently freely used in the study of endothelial cell biology without a clear definition, or even a consensus, of their meaning. Certainly, a continuum is likely to exist between endothelial activation (e.g. by cytokines), endothelial …

/pdf/assessment-of-endothelial-damage-and-dysfunction-3njyfrqj4v.pdf

Assessment of endothelial damage and dysfunction: observations in relation to heart failure.

The plasma thrombomodulin (TM) level depends on the integrity of the endothelium and the clearance of the molecule. In several different pathological conditions, plasma TM levels increase with damage to the endothelium. We studied plasma TM levels in patients with various localizations of atheromatous arterial disease who had normal serum creatinine levels. Two groups of patients had a single symptomatic localization, which was either peripheral occlusive arterial disease (POAD) or ischemic heart disease (B-ID) and a third group of patients had multiple symptomatic localizations (polyvascular). We compared the plasma TM levels with the plasma levels of other specific markers of endothelial cell activation such as : prostacyclin (PGIZ), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor @'AI-l). Plasma TM levels were significantly increased in all three individual groups and when all patients were considered (total patients), as compared with normal controls. When all patients were consider& there was a significant positive correlation between plasma TM levels and t-PA and between plasma TM levels and PGI2. A significant positive correlation was also found between the plasma TM levels and PAI-1 for patients with POAD. Thus, our findings suggest that an increased influx of TM into the plasma may be caused by endothelial cell damage in patients with atheromatous arterial disease. However in our study, the plasma TM levels obtained were similar for all three types of atheromatous arterial disease. Though plasma thrombomodulin is a marker of endothelial cell injury, it cannot be of a clinical interest until its levels am related to the extend of the atheromatous lesions. Moreover, we show that plasma TM is not independent of the usual endothelial cell activation markers.

LEVELS OF PLASMA TI-IROMBOMODULIN ARE INCREASED lN ATHEROMATOUS ARTERIAL DISEASE

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LEVELS OF PLASMA TI-IROMBOMODULIN ARE INCREASED lN ATHEROMATOUS ARTERIAL DISEASE