Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.

Drexler, Helmut; Fischell, Tim A.; Pinto, Fausto J.; Chenzbraun, Adrian; Botas, Javier; Cooke, John P.; Alderman, Edwin L.

doi:10.1161/01.cir.89.4.1615

Cited by 116 publications

(46 citation statements)

References 40 publications

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“…36 This observation is consistent with the hypothesis that endothelial vasodilator dysfunction in cardiac allograft recipients is mediated by ADMA. An impairment of NO synthesis and bioactivity would be predicted to have profound effects on vascular structure as well as function.…”

Section: CMV Adma and Transplant Arteriosclerosissupporting

confidence: 90%

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

et al. 2004

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Background-We hypothesized that cytomegalovirus (CMV) may contribute to the vasculopathy observed in cardiac allograft recipients by impairing the endothelial nitric oxide synthase pathway. We focused on asymmetric dimethylarginine (ADMA, the endogenous inhibitor of nitric oxide synthase) as a potential mediator of the adverse vascular effect of CMV. Methods and Results-Heart transplant recipients manifested elevated plasma ADMA levels compared with healthy control subjects. Transplant patients with CMV DNA-positive leukocytes had higher plasma ADMA concentrations and more extensive transplant arteriopathy (TA). Human microvascular endothelial cells infected with the CMV isolates elaborated more ADMA. The increase in ADMA was temporally associated with a reduction in the activity of dimethylarginine dimethylaminohydrolase (DDAH, the enzyme that metabolizes ADMA). Infected cultures showed high levels of oxidative stress with enhanced endothelial production of superoxide anion. Conclusions-CMV infection in human heart transplant recipients is associated with higher ADMA elevation and more severe TA. CMV infection in endothelial cells increases oxidative stress, impairs DDAH activity, and increases ADMA elaboration. CMV infection may contribute to endothelial dysfunction and TA by dysregulation of the endothelial nitric oxide synthase pathway. (Circulation. 2004;109:500-505.)

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Section: CMV Adma and Transplant Arteriosclerosissupporting

confidence: 90%

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

et al. 2004

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“…20,34 Since L-arginine is abundant in endothelial cells, 52 depletion of this substrate is not likely to account for the endothelial dysfunction. 53 It is possible that endogenous NO synthase inhibitors may contribute to endothelial dysfunction; indeed, after balloon injury of the rabbit iliac artery, the regenerated endothelium manifests a vasodilator dysfunction, associated with markedly elevated levels of intracellular ADMA.…”

Section: Plasma Adma and Atherosclerosismentioning

confidence: 99%

“…It is well known that L-arginine supplementation enhances the synthesis of endothelium-derived NO, 30 restores endothelial vasodilator function, [32][33][34] inhibits platelet aggregation 35,36 and cell adhesion, 20,[37][38][39][40] and attenuates atherosclerosis [41][42][43][44][45] in hypercholesterolemic animals and in humans. It is possible that L-arginine exerts these beneficial effects by reversing the action of the competitive inhibition by ADMA.…”

mentioning

confidence: 99%

Endogenous Nitric Oxide Synthase Inhibitor

et al. 1999

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Background-Exposure to risk factors such as hypertension or hypercholesterolemia decreases the bioavailability of endothelium-derived nitric oxide (NO) and impairs endothelium-dependent vasodilation. Recently, a circulating endogenous NO synthase inhibitor, asymmetric dimethylarginine (ADMA), has been detected in human plasma. The purpose of this study was to examine the relationship between plasma ADMA and atherosclerosis in humans. Methods and Results-Subjects (nϭ116; age, 52Ϯ1 years; male:female ratio, 100:16) underwent a complete history and physical examination, determination of serum chemistries and ADMA levels, and duplex scanning of the carotid arteries. These individuals had no symptoms of coronary or peripheral artery disease and were taking no medications. Univariate and multivariate analyses revealed that plasma levels of ADMA were positively correlated with age (PϽ0.0001), mean arterial pressure (PϽ0.0001), and ⌺ glucose (an index of glucose tolerance) (Pϭ0.0006). Most intriguingly, stepwise regression analysis revealed that plasma ADMA levels were significantly correlated to the intima-media thickness of the carotid artery (as measured by high-resolution ultrasonography). Conclusions-This study reveals that plasma ADMA levels are positively correlated with risk factors for atherosclerosis.Furthermore, plasma ADMA level is significantly correlated with carotid intima-media thickness. Our results suggest that this endogenous antagonist of NO synthase may be a marker of atherosclerosis.

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“…In allograft transplantation, eNOS expression and activity can be impaired by several factors including pre-existing disease in the graft, ischemia at the time of transplantation, immunosuppressive agents, and conventional risk factors such as hypertension, diabetes hyperlipidemia, and infections. Studies in heart transplant patients have demonstrated epicardial and microvascular coronary artery endothelial dysfunction (57,58). Specifically, paradoxical vasoconstriction in response to acetylcholine has been reported in up to 40% of patients early after transplant, an abnormality that persists long-term in some patients.…”

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 99%

“…Specifically, paradoxical vasoconstriction in response to acetylcholine has been reported in up to 40% of patients early after transplant, an abnormality that persists long-term in some patients. Reversibility of endothelial dysfunction by acute administration of L-arginine, the substrate for NO production, has been demonstrated (58). Endothelial dysfunction early after transplant has been shown to be a predictor of CAV (59), and adverse events in heart transplant patients (60,61).…”

Section: Impairment Of the Nitric Oxide Synthase Pathway In Cmv-inducmentioning

confidence: 99%

The Role of Viruses in Cardiac Allograft Vasculopathy

Valantine

2004

American Journal of Transplantation

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Considerable evidence suggests a role for viruses in transplant arteriosclerosis (TA), including observational data, experimental models and therapeutic trials implicating human cytomegalovirus (HCMV) in the progression to TA. In pediatric heart transplant patients, adenoviral genome in endomyocardial biopsies (EMB) is an important predictor of TA and graft loss. During CMV viremia, EMBs from adult patients demonstrate endothelialitis and vascular smooth muscle cell proliferation. These changes are predictors of subsequent diffuse TA. HCMV immediate early proteins (IE-1 and IE-2) increase the constitutive expression of intercellular adhesion molecule-1 (ICAM-1) independent of other intracellular cytokines. Likewise, viral chemokines such as US28 have been implicated in vascular disease because of their ability to induce smooth muscle cell migration. Recent data suggests that CMV might accelerate TA through its ability to abrogate the vascular protective effects of the endothelium-derived nitric oxide system (eNOS). Confirmation of causality requires clinical trials demonstrating that antiviral agents such as ganciclovir inhibit TA. Such studies in patients though limited to retrospective analyses, suggest that ganciclovir prophylaxis early after heart transplantation reduces the risk of TA. These observations emphasize the need for randomized controlled clinical trials to confirm a causal role for CMV (and other viruses) in TA.

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Effect of L-arginine on coronary endothelial function in cardiac transplant recipients. Relation to vessel wall morphology.

Cited by 116 publications

References 40 publications

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

Cytomegalovirus Infection Impairs the Nitric Oxide Synthase Pathway

Endogenous Nitric Oxide Synthase Inhibitor

The Role of Viruses in Cardiac Allograft Vasculopathy

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