Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease

Taylor, Lloyd M.; Moneta, Gregory L.; Sexton, Gary; Schuff, Robert; Porter, John M.

doi:10.1016/s0741-5214(99)70345-9

Cited by 165 publications

(88 citation statements)

References 34 publications

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“…39 In HHcy, flow-induced constriction of the arterioles may limit tissue blood supply, whereas the impaired of NO release and upregulated synthesis of TXA 2 in the endothelium, together with the simultaneously increased TXA 2 synthesis in platelets, 11,28 can substantially enhance platelet aggregation as well, favoring thrombus formation and leading to occlusive peripheral vascular disease, such as intermittent claudication. 2,3,40 In conclusion, the present study is the first to demonstrate that flow-dependent arteriolar dilation observed under normal healthy conditions is converted to constriction in HHcy rats. The constriction is due to the simultaneously impaired NO and enhanced TXA 2 mediation of arteriolar responses to increases in flow.…”

Section: February 2001supporting

confidence: 50%

“…Key Words: homocysteine Ⅲ arteriole Ⅲ flow-induced response Ⅲ endothelium Ⅲ nitric oxide Ⅲ thromboxane A 2 I ncreasing epidemiological and experimental evidence suggests that an elevated plasma level of homocysteine is associated with the development of peripheral arterial disease. [1][2][3][4][5] Homocysteine is a sulfur-containing amino acid that is formed during the metabolism of the essential amino acid methionine. 4 Plasma homocysteine concentration can be increased through alterations in genetic and nutritional factors, such as various enzyme (cystathione-␤-synthase, methyltetrahydrofolate reductase) abnormalities and deficiency of vitamins (folic acid, cyanocobalamin, pyridoxal phosphate), all of which participate in the metabolism of homocysteine and methionine (for further references, see Lentz et al 4 ).…”

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confidence: 99%

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Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Bagi

Ungvári

Szollár

et al. 2001

ATVB

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Abstract-Hyperhomocysteinemia (HHcy) is thought to promote arteriosclerosis and peripheral arterial disease, in part by impairing the function of endothelium. Because flow-induced dilation is mediated by the endothelium, we hypothesized that HHcy alters this response by interfering with the synthesis/action of NO and prostaglandins. Thus, changes in the diameter of isolated, pressurized (at 80 mm Hg) gracilis skeletal muscle arterioles (diameter Ϸ170 m) from control and methionine diet-induced HHcy rats were investigated with videomicroscopy. Increases in intraluminal flow (from 0 to 25 L/min) resulted in dilations of control arterioles (maximum, 34Ϯ4 m). In contrast, increases in flow elicited constrictions of HHcy arterioles (Ϫ36Ϯ3 m). In control arterioles, the NO synthase inhibitor N -nitro-L-argininemethyl ester significantly attenuated (Ϸ50%) dilation, whereas the additional administration of indomethacin, an inhibitor of cyclooxygenase, eliminated flow-induced dilation. In the arterioles of HHcy rats, flow-induced constriction was not affected by N -nitro-L-arginine-methyl ester, whereas it was abolished by indomethacin or the prostaglandin H 2 /thromboxane A 2 (TXA 2 ) receptor antagonist SQ 29,548 or the TXA 2 synthase inhibitor CGS 13,080. Thus, in HHcy, increases in intraluminal flow elicit constrictions of skeletal muscle arterioles due to the impaired NO and enhanced TXA 2 mediation of the response, alterations that likely contribute to the development of peripheral arterial disease. Key Words: homocysteine Ⅲ arteriole Ⅲ flow-induced response Ⅲ endothelium Ⅲ nitric oxide Ⅲ thromboxane A 2 I ncreasing epidemiological and experimental evidence suggests that an elevated plasma level of homocysteine is associated with the development of peripheral arterial disease. [1][2][3][4][5] Homocysteine is a sulfur-containing amino acid that is formed during the metabolism of the essential amino acid methionine. 4 Plasma homocysteine concentration can be increased through alterations in genetic and nutritional factors, such as various enzyme (cystathione-␤-synthase, methyltetrahydrofolate reductase) abnormalities and deficiency of vitamins (folic acid, cyanocobalamin, pyridoxal phosphate), all of which participate in the metabolism of homocysteine and methionine (for further references, see Lentz et al 4 ). Previously, several mechanisms have been suggested by which elevated homocysteine levels promote peripheral arterial disease, such as vascular smooth muscle proliferation, 6 platelet activation, 7 and endothelial injury. 7 It is likely that hyperhomocysteinemia (HHcy) impairs the vasoactive function of the endothelium of arteries and arterioles before the development of morphological changes. 8 -11 Indeed, the diminished increase in hindlimb circulation to acetylcholine in monkeys with diet-induced HHcy 8,9 suggests that the dilator capacity of small arteries and arterioles responsible for tissue vascular resistance is altered by HHcy. Also, we recently demonstrated that endothelium-dependent acetylcholine-a...

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Section: February 2001supporting

confidence: 50%

mentioning

confidence: 99%

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Bagi

Ungvári

Szollár

et al. 2001

ATVB

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“…Homocysteine, independent risk factor for arteriosclerosis and specifically coronary artery disease [43,44], has also been shown to increase levels of superoxide anion via the NADPH oxidase pathway [45]. However, it is not clear whether ceramide could be involved in homocysteine biological functions.…”

Section: Homocysteine and Ceramidementioning

confidence: 99%

Ceramide: A common pathway for atherosclerosis?

et al. 2008

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Plasma sphingomyelin concentration is correlated with the development of atherosclerosis. It has been found to exist in significantly higher concentrations in aortic plaque. This appears to have clinical relevance as well as it has been shown to be an independent predictor of coronary artery disease. Ceramide, the backbone of sphingolipids, is the key component which affects atherosclerotic changes through its important second-messenger role. This paper sheds light on some of the current literature supporting the significance of ceramide with respect to its interactions with lipids, inflammatory cytokines, homocysteine and matrix metalloproteinases. Furthermore, the potential therapeutic implications of modulating ceramide concentrations are also discussed.

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“…Studies have suggested that elevated Hcy concentrations are associated with an increased rate of stroke, coronary artery disease (CAD), peripheral vascular disease, and deep venous thrombosis. [3][4][5][6] …”

Section: Introductionmentioning

confidence: 99%

The association of homocysteine and coronary artery disease

Gauthier¹,

Keevil²,

McBride³

2003

Clinical Cardiology

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Summary: Hyperhomocysteinemia has been associated with increased risk of atherosclerosis and myocardial infarction by a number of prospective case-control studies. A variety of genetic mutations, nutritional deficiencies, disease states, and drugs can elevate homocysteine concentrations. Treatment with folic acid with or without B-complex vitamins effectively lowers homocysteine levels. Whether therapy corresponds with decreased risk of coronary events is unknown, but may be promising. This article reviews the biochemistry of homocysteine metabolism, pathogeneisis, and etiology of hyperhomocysteinemia, along with its association with coronary artery disease, screening, and treatment.

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Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease

Cited by 165 publications

References 34 publications

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Ceramide: A common pathway for atherosclerosis?

The association of homocysteine and coronary artery disease

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Prospective blinded study of the relationship between plasma homocysteine and progression of symptomatic peripheral arterial disease

Cited by 165 publications

References 34 publications

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A 2 Mediation

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A 2 Mediation

Ceramide: A common pathway for atherosclerosis?

The association of homocysteine and coronary artery disease

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Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation

Flow-Induced Constriction in Arterioles of Hyperhomocysteinemic Rats Is Due to Impaired Nitric Oxide and Enhanced Thromboxane A ₂ Mediation