- Email: [email protected]
101 XANTHINE OXIDASE INHIBITION IMPROVES ENDOTHELIAL FUNCTION DURING OXIDATIVE STRESS IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE
S58
Nutrition, Metabolism & Cardiovascular Diseases (2008) S35–S65
to investigate the relation between serum cholesterol levels and arterial stiffness. Methods: We determined lipid profile, BMI, blood pressure, heart rate, ECG, carotid IMT and parameters of arterial stiffness, including b-stiffness, elastic modulus (Ep), arterial compliance (AC), pulse wave velocity (PWV) and augmentation index (AIx), in 44 untreated subjects (16M/28F), mean age 10.7±2.8 years) with Hch (18 with FH and 26 with primary Hch) and 15 age and sex-matched controls. Results: No difference in blood pressure, heart rate, BMI, triglycerides and IMT values was found between the groups of subjects. In Hch subjects the values of b-stiffness, Ep, PWV and AIx were significantly higher (p < 0.001), whereas those of AC was lower (p < 0.01) respect to controls. b-stiffness, Ep, AC, PWV and AIx values were significantly correlated with plasma LDL-C levels (rs = 0.42, p < 0.001; rs = 0.45, p < 0.001, rs = 0.28, p < 0.05; rs = 0.41, p < 0.005; rs = 0.51, p < 0.001, respectively). Furthermore, the regression analysis showed a significant dependence between LDL-C levels and arterial stiffness values. Conclusion: Our findings shows that the values of carotid and systemic arterial stiffness are increased in asymptomatic, normotensive children with HCh, suggesting that HCh plays a key role in arterial endothelial modifications already since the pediatric age. 100 YOUNG ADULTS WITH CELIAC DISEASE MAY BE AT INCREASED RISK OF EARLY ATHEROSCLEROSIS A. Rigoni1 , S. De Marchi1 , M. Prior1 , G. Chiarioni2 , E. Arosio1 . 1 UO di Riabilitazione Vascolare, 2 UO di Gastroenterologia e Riabilitazione Gastrointestinale, Policlinico di Verona, Universit` a di Verona, Verona, Italy E-mail: [email protected] Introduction: Early atherosclerosis and increased cardiovascular risk have both been reported in immune-mediated rheumatology disorders [1 3], but few, controversial data are available in immune enteropathies. This risk seems to be related to systemic inflammation suggesting potential pathogenetic implications for other chronic inflammatory diseases [3]. However, literature data on the risk of death for cardiovascular diseases in celiac disease are few and controversial [4 6]. In addition, investigations on lipid profile provided data on potentially decreased HDL-cholesterol concentration, but no address on instrumental markers of early atherosclerosis in celiacs [7]. Patients and Methods: We evaluated prospectively instrumental and biochemical signs of atherosclerosis in 12 celiacs (7 females, 23 41 years) twice: at diagnosis, and after effective gluten withdrawal. Plasma totalHDL-LDL cholesterol, triglycerides, homocysteine, C-reactive protein (CRP), folate, and vitamin B12 were analyzed. Doppler evaluation of intima-media thickness at common carotid arteries (IMT) and endothelium dependent dilatation at humeral artery (EDD) were also carried on and compared with that of 22 matched healthy volunteers. Results: Mean total-HDL cholesterol were normal, but both parameters were increased by diet (p < 0.03 and < 0.001 respectively) with secondary improvement in total/HDL ratio (p < 0.02). Mean homocysteine was elevated (18.94±7.35 umol/l vn < 15), but not influenced by diet. CRP was significantly decreased (p < 0.05) by diet. IMT was increased (0.082±0.011 vs 0.058±0.012 cm p < 0.001) in celiacs compared to controls; gluten free diet was associated with a significant decrease in IMT (0.064±0.010 vs 0.082±0.011 cm; p < 0.003) gaining values almost overlapping with those of healthy volunteers (0.064±0.010 vs 0.058±0.012 cm; p = 0.61 ns). EDD was reduced in celiac patients compared to controls (9.3±1.3 vs 11.2±1.2%; p < 0.05) and recovered after dietetic intervention (12.7±2.1 vs 11.2±1.2%; p = 0.78 ns). Conclusions: In conclusion, our pilot study raises concerns on potentially increased cardiovascular risk in celiac disease secondary to accelerated atherosclerosis and unfavorable biochemical profile. Normalization of the small bowel mucosa due to gluten withdrawal seems to be associated with a beneficial effect also on vascular profile, in particular improving markers of cardiovascular risk (IMT and EDD). Further larger studies are warranted to better define cardiovascular risk factors in celiac disease and the potential positive modification induced by gluten abstinence. Reference(s) [1] Van Leuven SI; Kastelein JJ, D’Cruz DP, Hughes GR, Stroes ES. Atherogenesis in rheumatology. Lupus 2006; 15(3): 117 21. [2] Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lochshin MD, Sammaritano L, Devereux RB, Schwarz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Int Med 2006; 144(4): 249 256. [3] Hannawi S, Haluska B, Marwick TH, Thomas R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther 2007; 9(6): R116. [4] Viljama M, Kaurinen K, Pukkala E, Hervonen K, Reunala T, Collin P. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: a 30-year population-based study: Dig Liv Dis 2006; 38(6): 374 380. [5] West J, Logan RFA, Card TR, Smith C, Hubbard R. Risk of vascular disease in adults with diagnosed celiac disease: a population-based study. Aliment Pharmacol Ther 2004; 20(1): 83 79.
[6] Capristo E, Addolorato G, Mingrone G, Scarfone A, Greco A, Gasbarrini G. Low serum high density lipoprotein cholesterol concentration as a sign of celiac disease. Am J Gastroenterol 2000; 95(11): 3331 2. [7] Brar P, Kwon GY, Holleran S, Bai D, Tall AR, Ramakrishnan R, Green PHR. Change in lipid profile in celiac disease: beneficial effect of a gluten-free diet. Am J Med 2006; 119(9): 786 790. 101 XANTHINE OXIDASE INHIBITION IMPROVES ENDOTHELIAL FUNCTION DURING OXIDATIVE STRESS IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE A. Rigoni1 , S. De Marchi1 , M. Prior1 , P. Delva2 , E. Arosio1 . 1 UO di Riabilitazione Vascolare, 2 Medicina Interna C Policlinico di Verona, Universit` a di Verona, Verona, Italy E-mail: [email protected] Introduction: Xanthine oxidase is one of the main enzymatic systems producing reactive oxygen species [1], particularly during ischemiareperfusion phenomenon; in our protocol this model is the walking exercise on treadmill till the onset of ischemic pain (claudication) in patients with peripheral arterial disease [2]. In literature there are data about the production of oxidized species during strenuous physical exercise with enhanced glutathione consumption, oxidative damage, in particular through lipid peroxidation, leading to vascular dysfunction [3]. Our aim was to observe if xantine oxidase inhibition can prevent endothelial dysfunction induced by maximal exercise in patients affected with peripheral arterial disease and claudication intermittens (stage II of Fontaine) (PAD). The onset of pain in these patients is a sign of anaerobic exercise and ischemia, the succeeding recovery time is the reperfusion phase with relief of symptoms at the affected leg. Patients and Methods: We recruited 14 patients with PAD, 10 males and 4 females, aged 65 77 years. All of them have uric acid and lipidic prophile in normal range. Diabetic patients were not admitted, 11 were hypertensives with optimized therapy; no smokers were enrolled. Ankle-brachial index in the worse leg was between 0.62 and 0.81. They all underwent endothelial dependent dilation measurements at the brachial artery (EDD) by means of ultrasound and flux measurement of the femoral artery in the worse leg before and after maximal exercise on treadmill (speed 3.2 km/h; slope 10%). Allopurinol 600 mg was administered after the treadmill test and 600 mg the day after 6 hours before the second treadmill test. Uric acid was checked before and after protocol; lactate was dosed to confirm the patients reached anaerobic phase. Results: Maximal treadmill acutely reduced EDD (0.406±0.06 vs 0.442±0.06 cm; p < 0.005). Allopurinol improved EDD at rest (12.1±2.3 vs 7.3±1.2%; p < 0.05) and counteracted the reduction of EDD after maximal treadmill test ( 0.92±0.14 vs 2.5±0.23%; p < 0.05). Femoral artery flux increased after base exercise (0.702±0.012 vs 0.675±0.102 l/min; p < 0.05); a further increment in femoral artery flux after exercise was measured during treatment with allopurinol (0.714±0.011 vs 0.702±0.012 l/min; p < 0.05). Absolute walking distance after treatment increased (342±101 vs 228±98 m; p < 0.05). Uric acid was normal at baseline and reduced after treatment (3.55±1.22 vs 5.34±0.66 mg/dl; p < 0.005). Lactate increased after treadmill test, before and after allopurinol (baseline: 3.5±0.8 vs 1.3±0.3 mmol/l; p < 0.05 allopurinol: 3.4±1.1 vs 1.5±0.5 mmol/l; p < 0.05). Conclusions: Maximal treadmill test in PAD patients causes acutely endothelial dysfunction, it can be partially counteracted by administration of allopurinol. This drug reduces the generation of reactive oxygen species through inhibition of xanthine oxidase, as a consequence it improves EDD. The mechanism we can evoke for the increase of oxidative stress in this protocol is the ischemia-reperfusion damage that takes place in the affected leg during strenuous exercise. One of the most important mechanisms involved during ischemia-reperfusion phenomenon is the activation of xanthine oxidase [4]. Furthermore our study shows that allopurinol can increase femoral flux during exercise and walking distance; these effect cannot be attributed to reduction of uric acid [4]. In conclusion our study demonstrates that xanthine oxidase increase oxidative stress during maximal claudication and its inhibition improves peripheral haemodynamics, endothelial dysfunction and relieves symptoms. Reference(s) [1] Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction inchronic heart failure. Circulation 2002; 106: 221 6. [2] Andreozzi GM, Leone A, Laudani R, Deinite G, Martini R. Acute impairment of endothelial function by maximal treadmill exercise in patients with intermittent claudication, and its improvement after supervised physical training. Int Angiol 2007; 26: 12 7. [3] Heunks LMA, Vina J, Van Herwaarden CLA, Folgerin HTM, Gimeno A, Dekhuijzen PN. Xanthine oxidase is involved in exercise induced oxidative stress in chronic obstructive pulmonary disease. Am J Physiol 1999; 277: R1697 1704. [4] George J, Carr E, Davies J, Belch JJ, Struthers A. High dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006; 114: 2508 16.
Nutrition, Metabolism & Cardiovascular Diseases (2008) S35–S65
to investigate the relation between serum cholesterol levels and arterial stiffness. Methods: We determined lipid profile, BMI, blood pressure, heart rate, ECG, carotid IMT and parameters of arterial stiffness, including b-stiffness, elastic modulus (Ep), arterial compliance (AC), pulse wave velocity (PWV) and augmentation index (AIx), in 44 untreated subjects (16M/28F), mean age 10.7±2.8 years) with Hch (18 with FH and 26 with primary Hch) and 15 age and sex-matched controls. Results: No difference in blood pressure, heart rate, BMI, triglycerides and IMT values was found between the groups of subjects. In Hch subjects the values of b-stiffness, Ep, PWV and AIx were significantly higher (p < 0.001), whereas those of AC was lower (p < 0.01) respect to controls. b-stiffness, Ep, AC, PWV and AIx values were significantly correlated with plasma LDL-C levels (rs = 0.42, p < 0.001; rs = 0.45, p < 0.001, rs = 0.28, p < 0.05; rs = 0.41, p < 0.005; rs = 0.51, p < 0.001, respectively). Furthermore, the regression analysis showed a significant dependence between LDL-C levels and arterial stiffness values. Conclusion: Our findings shows that the values of carotid and systemic arterial stiffness are increased in asymptomatic, normotensive children with HCh, suggesting that HCh plays a key role in arterial endothelial modifications already since the pediatric age. 100 YOUNG ADULTS WITH CELIAC DISEASE MAY BE AT INCREASED RISK OF EARLY ATHEROSCLEROSIS A. Rigoni1 , S. De Marchi1 , M. Prior1 , G. Chiarioni2 , E. Arosio1 . 1 UO di Riabilitazione Vascolare, 2 UO di Gastroenterologia e Riabilitazione Gastrointestinale, Policlinico di Verona, Universit` a di Verona, Verona, Italy E-mail: [email protected] Introduction: Early atherosclerosis and increased cardiovascular risk have both been reported in immune-mediated rheumatology disorders [1 3], but few, controversial data are available in immune enteropathies. This risk seems to be related to systemic inflammation suggesting potential pathogenetic implications for other chronic inflammatory diseases [3]. However, literature data on the risk of death for cardiovascular diseases in celiac disease are few and controversial [4 6]. In addition, investigations on lipid profile provided data on potentially decreased HDL-cholesterol concentration, but no address on instrumental markers of early atherosclerosis in celiacs [7]. Patients and Methods: We evaluated prospectively instrumental and biochemical signs of atherosclerosis in 12 celiacs (7 females, 23 41 years) twice: at diagnosis, and after effective gluten withdrawal. Plasma totalHDL-LDL cholesterol, triglycerides, homocysteine, C-reactive protein (CRP), folate, and vitamin B12 were analyzed. Doppler evaluation of intima-media thickness at common carotid arteries (IMT) and endothelium dependent dilatation at humeral artery (EDD) were also carried on and compared with that of 22 matched healthy volunteers. Results: Mean total-HDL cholesterol were normal, but both parameters were increased by diet (p < 0.03 and < 0.001 respectively) with secondary improvement in total/HDL ratio (p < 0.02). Mean homocysteine was elevated (18.94±7.35 umol/l vn < 15), but not influenced by diet. CRP was significantly decreased (p < 0.05) by diet. IMT was increased (0.082±0.011 vs 0.058±0.012 cm p < 0.001) in celiacs compared to controls; gluten free diet was associated with a significant decrease in IMT (0.064±0.010 vs 0.082±0.011 cm; p < 0.003) gaining values almost overlapping with those of healthy volunteers (0.064±0.010 vs 0.058±0.012 cm; p = 0.61 ns). EDD was reduced in celiac patients compared to controls (9.3±1.3 vs 11.2±1.2%; p < 0.05) and recovered after dietetic intervention (12.7±2.1 vs 11.2±1.2%; p = 0.78 ns). Conclusions: In conclusion, our pilot study raises concerns on potentially increased cardiovascular risk in celiac disease secondary to accelerated atherosclerosis and unfavorable biochemical profile. Normalization of the small bowel mucosa due to gluten withdrawal seems to be associated with a beneficial effect also on vascular profile, in particular improving markers of cardiovascular risk (IMT and EDD). Further larger studies are warranted to better define cardiovascular risk factors in celiac disease and the potential positive modification induced by gluten abstinence. Reference(s) [1] Van Leuven SI; Kastelein JJ, D’Cruz DP, Hughes GR, Stroes ES. Atherogenesis in rheumatology. Lupus 2006; 15(3): 117 21. [2] Roman MJ, Moeller E, Davis A, Paget SA, Crow MK, Lochshin MD, Sammaritano L, Devereux RB, Schwarz JE, Levine DM, Salmon JE. Preclinical carotid atherosclerosis in patients with rheumatoid arthritis. Ann Int Med 2006; 144(4): 249 256. [3] Hannawi S, Haluska B, Marwick TH, Thomas R. Atherosclerotic disease is increased in recent-onset rheumatoid arthritis: a critical role for inflammation. Arthritis Res Ther 2007; 9(6): R116. [4] Viljama M, Kaurinen K, Pukkala E, Hervonen K, Reunala T, Collin P. Malignancies and mortality in patients with coeliac disease and dermatitis herpetiformis: a 30-year population-based study: Dig Liv Dis 2006; 38(6): 374 380. [5] West J, Logan RFA, Card TR, Smith C, Hubbard R. Risk of vascular disease in adults with diagnosed celiac disease: a population-based study. Aliment Pharmacol Ther 2004; 20(1): 83 79.
[6] Capristo E, Addolorato G, Mingrone G, Scarfone A, Greco A, Gasbarrini G. Low serum high density lipoprotein cholesterol concentration as a sign of celiac disease. Am J Gastroenterol 2000; 95(11): 3331 2. [7] Brar P, Kwon GY, Holleran S, Bai D, Tall AR, Ramakrishnan R, Green PHR. Change in lipid profile in celiac disease: beneficial effect of a gluten-free diet. Am J Med 2006; 119(9): 786 790. 101 XANTHINE OXIDASE INHIBITION IMPROVES ENDOTHELIAL FUNCTION DURING OXIDATIVE STRESS IN PATIENTS WITH PERIPHERAL ARTERIAL DISEASE A. Rigoni1 , S. De Marchi1 , M. Prior1 , P. Delva2 , E. Arosio1 . 1 UO di Riabilitazione Vascolare, 2 Medicina Interna C Policlinico di Verona, Universit` a di Verona, Verona, Italy E-mail: [email protected] Introduction: Xanthine oxidase is one of the main enzymatic systems producing reactive oxygen species [1], particularly during ischemiareperfusion phenomenon; in our protocol this model is the walking exercise on treadmill till the onset of ischemic pain (claudication) in patients with peripheral arterial disease [2]. In literature there are data about the production of oxidized species during strenuous physical exercise with enhanced glutathione consumption, oxidative damage, in particular through lipid peroxidation, leading to vascular dysfunction [3]. Our aim was to observe if xantine oxidase inhibition can prevent endothelial dysfunction induced by maximal exercise in patients affected with peripheral arterial disease and claudication intermittens (stage II of Fontaine) (PAD). The onset of pain in these patients is a sign of anaerobic exercise and ischemia, the succeeding recovery time is the reperfusion phase with relief of symptoms at the affected leg. Patients and Methods: We recruited 14 patients with PAD, 10 males and 4 females, aged 65 77 years. All of them have uric acid and lipidic prophile in normal range. Diabetic patients were not admitted, 11 were hypertensives with optimized therapy; no smokers were enrolled. Ankle-brachial index in the worse leg was between 0.62 and 0.81. They all underwent endothelial dependent dilation measurements at the brachial artery (EDD) by means of ultrasound and flux measurement of the femoral artery in the worse leg before and after maximal exercise on treadmill (speed 3.2 km/h; slope 10%). Allopurinol 600 mg was administered after the treadmill test and 600 mg the day after 6 hours before the second treadmill test. Uric acid was checked before and after protocol; lactate was dosed to confirm the patients reached anaerobic phase. Results: Maximal treadmill acutely reduced EDD (0.406±0.06 vs 0.442±0.06 cm; p < 0.005). Allopurinol improved EDD at rest (12.1±2.3 vs 7.3±1.2%; p < 0.05) and counteracted the reduction of EDD after maximal treadmill test ( 0.92±0.14 vs 2.5±0.23%; p < 0.05). Femoral artery flux increased after base exercise (0.702±0.012 vs 0.675±0.102 l/min; p < 0.05); a further increment in femoral artery flux after exercise was measured during treatment with allopurinol (0.714±0.011 vs 0.702±0.012 l/min; p < 0.05). Absolute walking distance after treatment increased (342±101 vs 228±98 m; p < 0.05). Uric acid was normal at baseline and reduced after treatment (3.55±1.22 vs 5.34±0.66 mg/dl; p < 0.005). Lactate increased after treadmill test, before and after allopurinol (baseline: 3.5±0.8 vs 1.3±0.3 mmol/l; p < 0.05 allopurinol: 3.4±1.1 vs 1.5±0.5 mmol/l; p < 0.05). Conclusions: Maximal treadmill test in PAD patients causes acutely endothelial dysfunction, it can be partially counteracted by administration of allopurinol. This drug reduces the generation of reactive oxygen species through inhibition of xanthine oxidase, as a consequence it improves EDD. The mechanism we can evoke for the increase of oxidative stress in this protocol is the ischemia-reperfusion damage that takes place in the affected leg during strenuous exercise. One of the most important mechanisms involved during ischemia-reperfusion phenomenon is the activation of xanthine oxidase [4]. Furthermore our study shows that allopurinol can increase femoral flux during exercise and walking distance; these effect cannot be attributed to reduction of uric acid [4]. In conclusion our study demonstrates that xanthine oxidase increase oxidative stress during maximal claudication and its inhibition improves peripheral haemodynamics, endothelial dysfunction and relieves symptoms. Reference(s) [1] Farquharson CA, Butler R, Hill A, Belch JJ, Struthers AD. Allopurinol improves endothelial dysfunction inchronic heart failure. Circulation 2002; 106: 221 6. [2] Andreozzi GM, Leone A, Laudani R, Deinite G, Martini R. Acute impairment of endothelial function by maximal treadmill exercise in patients with intermittent claudication, and its improvement after supervised physical training. Int Angiol 2007; 26: 12 7. [3] Heunks LMA, Vina J, Van Herwaarden CLA, Folgerin HTM, Gimeno A, Dekhuijzen PN. Xanthine oxidase is involved in exercise induced oxidative stress in chronic obstructive pulmonary disease. Am J Physiol 1999; 277: R1697 1704. [4] George J, Carr E, Davies J, Belch JJ, Struthers A. High dose allopurinol improves endothelial function by profoundly reducing vascular oxidative stress and not by lowering uric acid. Circulation 2006; 114: 2508 16.