Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study

Solh, Ali A. El; Saliba, Rima M.; Bosinski, Timothy J.; Grant, Brydon J. B.; Berbary, Eileen; Miller, Nicole P.

doi:10.1183/09031936.06.00101005

Cited by 108 publications

(108 citation statements)

References 38 publications

(37 reference statements)

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“…Previous studies reported that endothelial dysfunction in patients with OSA was reversible with administration of antioxidants (22,24). In this study, we found direct evidence of increased peroxynitrite production in the microcirculation of patients with OSA, providing an explanation for the role of antioxidants.…”

Section: Discussionsupporting

confidence: 65%

“…The mechanism of endothelial dysfunction in OSA is largely unknown. Endothelial dysfunction in OSA is reversible with antioxidants (22)(23)(24), suggesting a role for oxidant overproduction in the decreased NO availability in OSA. This provides parallels to other cardiovascular diseases in which oxidative stress-induced endothelial dysfunction is important (25,26).…”

mentioning

confidence: 93%

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Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Patt¹,

Jarjoura²,

Haddad³

et al. 2010

Am J Respir Crit Care Med

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Rationale: Obstructive sleep apnea (OSA) is a risk factor for cardiovascular disease. We hypothesized that patients with OSA and no cardiovascular disease have oxidant-related microcirculatory endothelial dysfunction. Objectives: To evaluate the microcirculation in OSA. Methods: This study included seven patients with OSA and seven ageand weight-matched control subjects (mean age, 38 yr; mean body mass index, 32.5 kg/m 2 ). All participants were free of cardiovascular risk factors. Participants received measurement of brachial artery flow-mediated dilation and forearm subcutaneous biopsy. Patients underwent repeated tests 12 weeks after treatment. Microcirculatory endothelial cells were isolated, and immunohistochemistry staining for peroxynitrite in the microcirculation was performed. Measurements and Main Results: Flow-mediated dilation was lower in patients than in control subjects at baseline (mean 6 SEM: 5.7 6 0.5 vs. 9.5 6 0.6; P 5 0.02) and increased after treatment (5.7-7.3; change, 1.7 6 0.6; P 5 0.04). Microcirculatory peroxynitrite deposit was higher in patients compared with control subjects (44.0 6 1.6 vs. 21.8 6 1.9 stain density units; P , 0.001) and decreased after treatment from 44.0 to 30.5 stain density units (change, 213.5 6 2.9; P 5 0.009). In patients, transcription of endothelial nitric oxide synthase decreased from 5.2 to 21.3 after treatment (change, 6.5 6 2.5; P 5 0.05), and transcription of superoxide dismutase1 decreased from 24.0 to 212.3 after treatment (change, 28.3 6 2.1; P 5 0.01). These changes persisted after adjustment for weight and underlying severity of OSA. Conclusions: This is the first direct evaluation of the microcirculation in OSA. Patients with OSA with low cardiovascular risk status had increased oxidant production in the microcirculation and endothelial dysfunction, both of which improved with treatment. Endothelial nitric oxide synthase transcription decreased with treatment.

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Section: Discussionsupporting

confidence: 65%

mentioning

confidence: 93%

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Patt¹,

Jarjoura²,

Haddad³

et al. 2010

Am J Respir Crit Care Med

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“…Several studies have reported an inverse relationship between uric acid and endothelial function/ FMD (13,18 -21), although this has not uniformly been noted (22). A number of studies have also reported that lowering uric acid with allopurinol may improve endothelial function in individuals with a variety of conditions, including subjects with heart failure (23-25), those with diabetes (26), heavy smokers (27), or those with obstructive sleep apnea (28). However, to our knowledge, only one study examined the effect of allopurinol on endothelial function in subjects with asymptomatic hyperuricemia (13).…”

Section: Discussionmentioning

confidence: 68%

A Randomized Study of Allopurinol on Endothelial Function and Estimated Glomular Filtration Rate in Asymptomatic Hyperuricemic Subjects with Normal Renal Function

Kanbay

Huddam

Azak

et al. 2011

Clinical Journal of the American Society of Nephrology

231

181

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SummaryBackground and objectives Endothelial dysfunction is an early manifestation of vascular injury and contributes to the development of atherosclerotic cardiovascular disease. Recent studies have implicated hyperuricemia as a risk factor for cardiovascular disease. We hypothesized that lowering uric acid in subjects with asymptomatic hyperuricemia with allopurinol might improve endothelial dysfunction, BP, estimated GFR (eGFR), and inflammatory markers.Design, setting, participants, & measurements Subjects with asymptomatic hyperuricemia and no history of gout and 30 normouricemic control subjects were enrolled in this 4-month randomized prospective study. Thirty hyperuricemic patients received 300 mg/d allopurinol and were compared with 37 hyperuricemic patients and 30 normouricemic subjects in matched control groups. Flow-mediated dilation (FMD), eGFR, ambulatory BP monitoring, spot urine protein-creatine ratio, and highly sensitive C-reactive protein were measured at baseline and at 4 months.Results Age, gender, lipid profile, eGFR, hemoglobin, glucose, and level of proteinuria were similar in hyperuricemic subjects and controls at baseline. As expected, hyperuricemic patients had higher levels of highly sensitive C-reactive protein and lower FMD compared with normouricemic patients. Allopurinol treatment resulted in a decrease in serum uric acid, a decrease in systolic BP, an increase in FMD, and an increase in eGFR compared with baseline. No significant difference was observed in the control hyperuricemic and normouricemic groups. In a multiple regression analysis, FMD levels were independently related to uric acid both before (beta ϭ Ϫ0.55) and after (beta ϭ Ϫ0.40) treatment.Conclusions Treatment of hyperuricemia with allopurinol improves endothelial dysfunction and eGFR in subjects with asymptomatic hyperuricemia.

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“…However, most clinical research has studied the correlation of this impact via therapeutic interventions without analyzing causality (10,25,26). Other studies have shown improvements in oxidative stress with CPAP treatment (7,(27)(28)(29)(30).…”

Section: Discussionmentioning

confidence: 99%

“…Malondialdehyde (MDA) is a lipid peroxidation marker, commonly used in human pathology (10)(11)(12). P-selectin is largely responsible for the rolling phase of the leukocyte adhesion cascade (13).…”

Section: Introductionmentioning

confidence: 99%

Association of Cellular Adhesion Molecules and Oxidative Stress with Endothelial Function in Obstructive Sleep Apnea

et al. 2012

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Objective To evaluate the impact of oxidative stress and cellular adhesion molecules on ischemic reactive hyperemia (IRH) in patients with OSA. Materials and MethodsConsecutive patients treated at a sleep laboratory and whose polysomnography showed an apnea hypopnea index (AHI) " 5 were included in the study. Patients with acute illness receiving vasoactive medications were excluded. Based on their oxygen desaturation index (ODI), subjects were assigned to the mild-moderate (ODI !30) or the severe desaturation group (ODI >30). Then IRH and oxidative stress markers [malondialdehyde (MDA)] and proinflammatory markers (ICAM-1 and P-selectin) were measured. Results Sixty-eight subjects with OSA were included, 31 in the mild-moderate desaturation group and 37 in the severe group. No differences by age, gender and body mass index were observed. The severe desaturation group showed significantly higher values in the AHI, MDA, ICAM-1 and P-selectin (p<0.005), as well as a worsening of IRH (p=0.001). Only ICAM-1 (p=0.019) and P-selectin (p=0.033) were independently associated with IRH in a multiple-linear regression model. Conclusion Patients with OSA and greater intermittent hypoxia showed worse endothelial function, and higher levels of MDA, ICAM-1 and P-selectin. Nevertheless, ICAM-1 and P-selectin rather than MDA were independently associated with IRH.

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Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study

Cited by 108 publications

References 38 publications

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

Endothelial Dysfunction in the Microcirculation of Patients with Obstructive Sleep Apnea

A Randomized Study of Allopurinol on Endothelial Function and Estimated Glomular Filtration Rate in Asymptomatic Hyperuricemic Subjects with Normal Renal Function

Association of Cellular Adhesion Molecules and Oxidative Stress with Endothelial Function in Obstructive Sleep Apnea

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