Jonathan Goodfellow

Dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia

OBJECTIVE This work was undertaken to determine whether dietary supplementation with marine omega-3 fatty acids improve systemic large artery endothelial function in subjects with hypercholesterolemia. BACKGROUND Marine omega-3 fatty acids improve vascular function, but the underlying mechanism(s) are unclear. We studied the effects of marine omega-3 fatty acids on large artery endothelial function in subjects with hypercholesterolemia. METHODS Hypercholesterolemic subjects with no other known cause for endothelial dysfunction were recruited to a prospective, placebo-controlled, randomized, double-blind, parallel-group study. Treatment with omega-3 fatty acids at a dose of 4 g/day (n = 15/group) was compared with placebo, at the beginning (day 0) and end (day 120) of a four-month treatment period. Endothelial function was assessed pre- and posttreatment by noninvasive ultrasonic vessel wall tracking of brachial artery flow-mediated dilation (FMD). RESULTS Treatment with marine omega-3 fatty acids resulted in a significant improvement in FMD (0.05 +/- 0.12 to 0.12 +/- 0.07 mm, p < 0.05) and a significant reduction in triglycerides (2.07 +/- 1.13 to 1.73 +/- 0.95 mmol/liter, p < 0.05), whereas treatment with placebo resulted in no change in FMD (0.03 +/- 0.10 to 0.04 +/- 0.10 mm) or triglycerides (2.29 +/- 2.09 to 2.05 +/- 1.36 mmol/liter) (both p < 0.05 treated compared with control). Responses to sublingual glyceryl trinitrate were unchanged. CONCLUSIONS Marine omega-3 fatty acids improve large artery endothelium-dependent dilation in subjects with hypercholesterolemia without affecting endothelium-independent dilation.

Endothelial Control of Arterial Distensibility Is Impaired in Chronic Heart Failure

BACKGROUND Vascular tone is a determinant of conduit artery distensibility. The aim of this study was to establish whether endothelium-derived relaxing factor (EDRF) influences the distensibility of conduit arteries and whether endothelium-mediated increases in distensibility are impaired in chronic heart failure (CHF). METHODS AND RESULTS Conduit artery distensibility was measured by two methods in healthy subjects and in nine patients with CHF caused by dilated cardiomyopathy. In the first method, pulse-wave velocity (PWV) was measured in the right common iliac artery at rest and during local infusions of acetylcholine (10(-7) to 10(-5) mol/L) or adenosine (2 x 10(-7) to 2 x 10(-5) mol/L), with correction for systemic effects. Acetylcholine induced concentration-dependent local reductions of PWV in healthy subjects (-5%, -15%, and -26%) but not in CHF patients (3%, 1%, -4%, P < .01), whereas adenosine induced similar reductions of PWV in healthy subjects and CHF patients. In the second method, brachial artery diameter, blood flow, and blood pressure were measured noninvasively by high-resolution ultrasound, continuous-wave Doppler, and photoplethysmography during reactive hyperemia in the hand and after sublingual glyceryl trinitrate (GTN, 400 micrograms). Hyperemic flow, similar in healthy subjects and CHF patients, was associated with increases in diameter and distensibility in healthy subjects (8.8% and 18.4%, respectively) but not in CHF patients (0.3% and -4.5%), whereas GTN induced similar effects in healthy subjects and CHF patients. CONCLUSIONS These data indicate that conduit artery distensibility is increased by acetylcholine and increased blood flow in healthy subjects but not in CHF patients, whereas the effects of adenosine and GTN on distensibility are preserved in CHF patients. This implies that EDRF-mediated increases in distensibility are impaired in CHF patients, thus adding to cardiac work.

Endothelium and inelastic arteries: an early marker of vascular dysfunction in non-insulin dependent diabetes.

Atheroma is the main cause of mortality and morbidity in patients with non-insulin dependent diabetes mellitus. Endothelial dysfunction underlies atheroma formation. Flow mediated vasodilatation is a measure of endothelial function as well as a determinant of arterial distensibility,1 measurements of which have not previously been reported in patients with non-insulin dependent diabetes. We studied 12 symptom free, non-smoking, healthy patients (six men) with well controlled non-insulin dependent diabetes diabnosed 1-7 (mean 3.8) years previously (mean age 50 (SD 9) years, body mass index 26.9 (4.8) kg/m2, serum cholesterol concentration 5.8 (0.5) mmol/l). Patients with known causes of endothelial dysfunction were excluded. All patients had insulin resistance with basal hyperinsulinaemia,2 no biochemical evidence of renal impairment, and no microalbuminuria. A group of 12 normal non-smoking subjects was matched for sex, age, body mass index, blood …

High- but not low-dose folic acid improves endothelial function in coronary artery disease

Background  While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated.

Is the fatty meal a trigger for acute coronary syndromes

This hypothesis paper aims to illustrate the role of fatty meal ingestion has on the vascular endothelium and coagulation system. In particular highlighting the potential risk of fatty meal ingestion both as a trigger to an adverse factor in patients with acute coronary syndromes. We propose that as a result of ingesting fatty meals as a part of daily living, there occurs a constellation of changes in the vasculature that results in both a hypercoagulable and a provasoconstrictor state. These acute changes in response to a fatty meal on endothelial function, prothrombosis, and platelet activation can potentially trigger, facilitate and propagate the forces that drive acute coronary syndromes. In type 2 diabetes, adverse postprandial phenomena are exaggerated and prolonged and may therefore be expected to contribute significantly to the excess risk of acute coronary syndromes and atherosclerotic development in these subjects.

Lowering plasma homocysteine with folic acid in cardiovascular disease: what will the trials tell us?

Lowering plasma homocysteine with folic acid in cardiovascular disease: what will the trials tell us? Sagar N. Doshi , Stuart J. Moat *, Ian F.W. McDowell , Malcolm J. Lewis , Jonathan Goodfellow d a Cardiovascular Institute, Mount Sinai School of Medicine, New York, USA b Department of Pharmacology, Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK c Department of Medical Biochemistry, Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK d Department of Cardiology, Cardiovascular Sciences Research Group, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff, CF14 4XN, UK

Homocysteine and endothelial function

See article of Lambert et al. [34] (pages 743–751) in this issue. The hypothesis that homocysteine may cause vascular disease was originally proposed by McCully, following the observation that premature thromboembolism and atherosclerosis was a feature of homocystinuria [1]. In homocystinuria, a rare inborn error of metabolism, plasma homocysteine concentrations are generally 10 to 50 times that found in the healthy population [2]. This led to the hypothesis that mild to moderate elevations of plasma homocysteine may be a risk factor for atherosclerosis in the general population. This hypothesis has generated considerable interest, particularly as simple therapy with oral B group vitamins significantly lowers plasma homocysteine [3]. Homocysteine is a thiol containing amino acid that is metabolised from methionine, an essential amino acid derived from dietary protein. Homocysteine can be metabolised further to cysteine by transsulfuration (using vitamin B6 as cofactor) or remethylated back to methionine using either methyltetrahydrofolate (and Vit B12 as cofactor) or betaine as co-substrate (see Fig. 1). In human plasma, homocysteine exists in several forms. Approximately 70–80% is bound to protein, mainly albumin, by a disulphide bond. The remaining homocysteine oxidises to form dimers (homocystine) or combines with cysteine to form a mixed disulphide. Only a small proportion (<1%) circulates as free homocysteine. A number of techniques are now available for the combined measurement of the multiple forms of plasma homocysteine, which is expressed as total homocysteine (tHcy) [4]. Fig. 1 Metabolism of homocysteine. A ‘normal’ range for tHcy cannot be defined but various studies report fasting levels in the range 5–15 μmol/l in the healthy population. A number of factors, genetic and acquired, can influence the blood levels of tHcy. Genetic factors include the genotype for methylene tetrahydrofolate reductase (MTHFR) C677T mutation, which results in thermolability, reduced activity and consequently fasting hyperhomocysteinaemia, particularly … * Corresponding author. Tel.: +44-1222-744-851; fax: +44-1222-766-276

Folate improves endothelial function in patients with coronary heart disease

Abstract Elevated plasma homocysteine is associated with increased cardiovascular risk but it remains unproven that the effect is directly causal. Folate and homocysteine metabolism are closely linked such that administration of folic acid in doses ranging from 0.2–10 mg/day lowers plasma total homocysteine (tHcy) by up to 25%. Folic acid has been widely advocated as a therapy which may reduce cardiovascular risk, but the clinical benefit remains as yet unproven and the choice of dose remains unclear. The effect of folic acid on endothelial function has been investigated in patients with proven coronary heart disease (CHD) by measuring flow-mediated dilatation (FMD) in the brachial artery. Oral folic acid (5 mg/day) markedly enhances endothelial function (FMD) and lowers homocysteine. Studies of the acute effects of folic acid have shown that this improvement occurs within the first 2–4 hours following the first dose, at which times there was no significant reduction in plasma tHcy. Administration of 5-methyltetrahydrofolate directly into the brachial artery markedly enhances FMD, an effect that is blocked by monomethyl arginine (LNMMA), suggesting that the effects of folate are mediated by nitric oxide. This Review summarises studies which show that pharmacological doses of folate markedly enhance endothelial function in patients with CHD. The discordance with changes in plasma homocysteine suggests that these effects may occur by mechanisms distinct from homocysteine lowering.

Improving endothelial vasomotor function

The vascular endothelium is a confluent, cellular monolayer that lines the entire vascular compartment at the interface between blood and the vessel wall. This “organ” possesses complex endocrine and paracrine functions and is intimately concerned in controlling vasomotor tone and preventing atherosclerosis and thrombosis.1 Indeed, endothelial dysfunction plays a key part in the pathogenesis and progression of atherosclerosis.2 An important and relatively recently discovered endothelial product is nitric oxide, a simple, highly reactive gas previously known as endothelium-derived relaxing factor. Endothelial nitric oxide itself possesses potent antiatherogenic properties, inhibits platelet aggregation, and regulates vascular tone.1 Bioavailable nitric oxide may be increased either by enhancing its production or by reducing its inactivation—for example, by reactive oxygen species, which are thought to damage the endothelium and promote atherosclerosis. Indirect measurement of bioavailable nitric oxide, through its vasodilating properties, is an extensively investigated surrogate of endothelial (vasomotor) function in clinical and experimental studies. In this …

Cardiovascular Syndromes X, endothelial dysfunction and insulin resistance

Cardiac Syndrome X (microvascular angina) and the more recently described metabolic Syndrome X (an epidemiological association between insulin resistance and atheroma, dyslipidaemia, and hypertension) may have more in common than the chance of their common sobriquet, in view of evidence that microvascular angina too is characterised by insulin resistance and endothelial dysfunction. The implications are discussed.