Asymmetric dimethylarginine and long-term adverse cardiovascular events in patients with type 2 diabetes: relation with the glycemic control

Cardiovascular Diabetology

Tse-Min Lu²  Shing-Jong Lin¹  Ming-Yi Chung⁴  Pai-Feng Hsu²  Chiao-Po Hsu³ 

[1] Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan;Division of Cardiology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan;School of Medicine, National Yang-Ming University, Taipei, Taiwan;Department of Life Sciences and Institute of Genome Sciences, National Yang-Ming University, Taipei, Taiwan

关键词: Nitric oxide;    Hemoglobin A1c;    Diabetes;    Asymmetric dimethylarginine;   

Others  :  1118931
DOI  :  10.1186/s12933-014-0156-1

 received in 2014-08-29, accepted in 2014-11-12,  发布年份 2014

【 摘 要 】

Background and aims

Elevated plasma asymmetric dimethylarginine (ADMA) levels have been observed in patients with insulin resistance and diabetes, and have been reported to predict adverse cardiovascular events in type 2 diabetic patients. However, the relationship between ADMA and glycemic control in patients with type 2 diabetes remained controversial.

Methods and results

We evaluated 270 patients with type 2 diabetes and measured their plasma ADMA and hemoglobin A1c (HbA1c) levels by high performance liquid chromatography. The mean age was 67 ± 12 years. The mean plasma ADMA and HbA1c level were 0.46 ± 0.09 μmol/l and 7.8 ± 1.6%, respectively. There was no significant correlation between plasma ADMA level and HbA1c level (r = −0.09, p = 0.13). During the median follow-up period of 5.7 years (inter-quartile range: 5.0 − 7.3 years), major adverse cardiovascular event (MACE, including cardiovascular death, myocardial infarction and stroke) was observed in 55 patients (20.4%). Multivariate Cox regression analysis revealed that the ADMA tertile was an independent risk factor for MACE (ADMA tertile III versus ADMA tertile I: p = 0.026, HR: 2.31, 95% CI: 1.10 − 4.81). The prognosis predictive power of ADMA disappeared in patients with well glycemic control (HbA1c ≤6.5%), and the ADMA-HbA1c interaction p value was 0.01.

Conclusions

In patients with type 2 diabetes, ADMA might be an independent risk factor for long-term adverse cardiovascular events. However, ADMA was not correlated with serum HbA1c level, and in diabetic patients with HbA1c ≤6.5%, elevated ADMA level was no longer associated with increased risk of long-term prognosis. Our findings suggested that the prognosis predictive value of ADMA in type 2 diabetes might be modified by the glycemic control.

【 授权许可】

   
2014 Hsu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M: Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998, 339:229-234.
• [2]Schalkwijk CG, Stehouwer CD: Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci 2005, 109:143-159.
• [3]Steinberg HO, Brechtel G, Johnson A, Fineberg N, Baron AD: Insulin-mediated skeletal muscle vasodilation is nitric oxide dependent. A novel action of insulin to increase nitric oxide release. J Clin Invest 1994, 94:1172-1179.
• [4]Vincent MA, Clerk LH, Lindner JR, Klinbanov AL, Clark MG, Ratiggan S, Barrett EJ: Microvascular recruitment is an early insulin effect that regulates skeletal muscle glucose uptake in vivo. Diabetes 2004, 53:1418-1423.
• [5]Kakimoto Y, Akazawa S: Isolation and identification of NG, NG- and NG, N’G dimethyl-arginine, Ne-mono-, di-, and trimethyllysine, glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. J Biol Chem 1970, 245:5751-5758.
• [6]Vallance P, Leone A, Calver A, Collier J, Moncada S: Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet 1992, 339:572-575.
• [7]Leiper J, Vallance P: Biological significance of endogenous methylarginines that inhibit nitric oxide synthases. Cardiovasc Res 1999, 43:542-548.
• [8]Böger RH, Bode-Böger SM, Tsao PS, Lin PS, Chan JR, Cooke JP: An endogenous inhibitor of nitric oxide synthase regulates endothelial adhesiveness for monocytes. J Am Coll Cardiol 2000, 36:2287-2295.
• [9]Stühlinger MC, Abbasi F, Chu JW, Lamendola C, McLaughlin TL, Cooke JP, Reaven GM, Tsao PS: Relationship between insulin resistance and an endogenous nitric oxide synthase inhibitor. JAMA 2002, 287:1420-1426.
• [10]Abbasi F, Asagmi T, Cooke JP, Lamendola C, McLaughlin T, Reaven GM, Stühlinger M, Tsao PS: Plasma concentrations of asymmetric dimethylarginine are increased in patients with type 2 diabetes mellitus. Am J Cardiol 2001, 88:1201-1203.
• [11]Altinova AE, Arslan M, Sepici-Dincel A, Akturk M, Altan N, Toruner FB: Uncomplicated type 1 diabetes is associated with increased asymmetric dimethylarginine concentrations. J Clin Endocrinol Metab 2007, 92:1881-1885.
• [12]Krzyzanowska K, Mittermayer F, Krugluger W, Schnack C, Hofer M, Wolzt M, Schernthaner G: Asymmetric dimethylarginine is associated with macrovascular disease and total homocysteine in patients with type 2 diabetes. Atherosclerosis 2006, 189:236-240.
• [13]Abhary S, Kasmeridis N, Burdon KP, Kuot A, Whiting MJ, Yew WP, Petrovsky N, Craig JE: Diabetic retinopathy is associated with elevated serum asymmetric and symmetric dimethylarginines. Diabetes Care 2009, 32:2084-2086.
• [14]Hanai K, Babazono T, Nyumura I, Toya K, Tanaka N, Tanaka M, Ishii A, Iwamoto Y: Asymmetric dimethylarginine is closely associated with the development and progression of nephropathy in patients with type 2 diabetes. Nephro Dial Transplant 2009, 24:1884-1888.
• [15]Krzyzanowska K, Wolzt M, Mittermayer F, Schernthaner G: Asymmetric dimethylarginine predicts cardiovascular events in patients with type 2 diabetes. Diabetes Care 2007, 30:1834-1839.
• [16]Lajer M, Teerlink T, Tarnow L, Parving H, Jorsal A, Rossing P: Plasma concentration of asymmetric dimethylarginine (ADMA) predicts cardiovascular morbidity and mortality in type 1 diabetic patients with diabetic nephropathy. Diabetes Care 2008, 31:747-752.
• [17]Cavusoglu E, Ruwende C, Chopra V, Poludasu S, Yanamadala S, Frishman WH, Eng C, Pinsky DJ, Marmur JD: Relation of baseline ADMA levels to cardiovascular morbidity and mortality at two years in men with diabetes referred for coronary angiography. Atherosclerosis 2010, 210:226-231.
• [18]Päivä H, Lehtimäki , Laakso J, Ruokonen I, Rantaiho V, Wirta O, Pasternack A, Laaksonen R: Plasma concentrations of asymmetric dimethylarginine in type 2 diabetes associated with glycemic control and glomerular filtration rate but not with risk factors of vasculopathy. Metabolism 2003, 52:303-307.
• [19]Böger RH, Sullivan LM, Schwedhelm E, Wang TJ, Maas R, Benjamin EJ, Schulze F, Xanthakis V, Benndorf RA, Vasan RS: Plasma asymmetric dimethylarginine and incidence of cardiovascular disease and death in the community. Circulation 2009, 119:1592-1600.
• [20]Devangelio E, Santilli F, Formoso G, Ferroni Bucciarelli L, Michetti N, Clissa C, Ciabattoni G, Consoli A, Davi G: Soluble RAGE in type 2 Diabetes: association with oxidative stress. Free Radial Biol Med 2007, 43:511-518.
• [21]Marcovecchio ML, Widmer B, Turner C, Dunger B, Dalton RN: Asymmetric dimethylarginine in young people with type 1 diabetes: a paradoxical association with HbA1c. Diabetic Med 2011, 28:685-691.
• [22]Marcovecchio ML, Widmer B, Dunger B, Dalton RN: Effect of acute variations of insulin and glucose on plasma concentrations of asymmetric dimethylarginine in young people with type 1 diabetes. Clin Sci 2008, 115:361-369.
• [23]Follow-up report on the diagnosis of diabetes mellitus Diabetes Care 2003, 26:3160-3167.
• [24]Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jones DW, Materson BJ, Oparil S, Wright JT, Roccella EJ: The seventh report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure. JAMA 2003, 289:2560-2571.
• [25]Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC: Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003, 24:1912-1919.
• [26]Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, Xu JS, Huang SM, Wang LN, Huang W, Wang M, Xu GB, Wang HY: Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 2006, 17:2937-2944.
• [27]Hamed S, Brenner B, Aharon A, Daoud D, Roguin A: Nitric oxide and superoxide dismutase modulate endothelial progenitor cell function in type 2 diabetes mellitus. Cardiovasc Diabetol 2009, 8:56. BioMed Central Full Text
• [28]Sydow K, Mondon CE, Schrader J, Konishi H, Cooke JP: Dimethylarginine dimethylaminohydrolase overexpression enhances insulin sensitivity. Arterioscler Thromb Vasc Biol 2008, 28:692-697.
• [29]Mclaughlin T, Stühlinger M, Lamendola C, Abbasi F, Bilek J, Reaven GM, Tsao PS: Plasma asymmetric dimethylarginine concentrations are elevated in obese insulin-resistant women and fall with weight loss. J CLin Endocrine Metab 2006, 91:1896-1900.
• [30]Deftereos S, Bouras G, Tsounis D, Papadimitriou C, Hatzis G, Raisakis K, Panagopoulou V, Kaoukis A, Ioannidis A, Deftereos G, Kossyvakis C, Manolis AS, Alexopoulos D, Stefanadis C, Cleman MW, Giannopoulos G: Association of asymmetric dimethylarginine levels with treadmill-stress-test-derived prognosticators. Clin Biochem 2014, 47:593-598.
• [31]Riccioni G, Scotti L, D'Orazio N, Gallina S, Speziale G, Speranza L, Bucciarelli T: ADMA/SDMA in elderly subjects with asymptomatic carotid atherosclerosis: values and site-specific association. Int J Mol Sci 2014, 15:6391-6398.
• [32]Protopsaltis I, Foussas S, Angelidi A, Gritzapis A, Sergentanis T, Matsagos S, Tzirogiannis K, Panoutsopoulos GI, Dimitriadis G, Raptis S, Melidonis A: Impact of ADMA, endothelial progenitor cells and traditional cardiovascular risk factors on pulse wave velocity among prediabetic individuals. Cardiovasc Diabetol 2012, 11:141. BioMed Central Full Text
• [33]Surdacki A, Kruszelnicka O, Rakowski T, Jaźwińska-Kozuba A, Dubiel JS: Asymmetric dimethylarginine predicts decline of glucose tolerance in men with stable coronary artery: a 4.5-year follow-up study. Cardiovasc Diabetol 2013, 12:64. BioMed Central Full Text
• [34]Kruszelnicka O, Surdacki A, Golay A: Differential associations of angiographic extent and severity of coronary artery disease with asymmetric dimethylarginine but not insulin resistance in non-diabetic men with stable angina: a cross-sectional study. Cardiovasc Diabetol 2013, 12:145. BioMed Central Full Text
• [35]Jawalekar SL, Karnik A, Bhutey A: Risk of cardiovascular disease in diabetes mellitus and serum concentration of asymmetrical dimethylarginine.Biochem Res Int 2013, 189430.
• [36]Meinitzer A, Seelhorst U, Wellnitz B, Halwachs-Baumann G, Boehm B, Winkelmann BR, März W: Asymmetrical dimethylarginine independently predicts total cardiovascular mortality in individuals with angiographic coronary artery disease (The Ludwigshafen risk and cardiovascular health study). Clin Chem 2007, 53:273-283.
• [37]Anderssohn M, McLachlan S, Lüneburg N, Robertson C, Schwedhelm E, Williamson RM, Strachan MW, Ajjan R, Grant PJ, Böger RH, Price JF: Genetic and environmental determinants of dimethylarginines and association with cardiovascular disease in patients with type 2 diabetes. Diabetes Care 2014, 37:846-854.
• [38]Sibal L, Agarwal SC, Schwedhelm E, Lüneburg N, Böger RH, Home PD: A study of endothelial function and circulating asymmetric dimethylarginine levels in people with type I diabetes without macrovascular disease or macroalbuminuria. Cardiovasc Diabetol 2009, 8:27. BioMed Central Full Text
• [39]Anderssohn M, Schwehelm E, Lüneburg N, Vasan SR, Böger RH: Asymmetric dimethylarginine as a mediator of vascular dysfunction and a marker of cardiovascular disease and mortality: an intriguing interaction with diabetes mellitus. Diabetes Vasc Dis Res 2010, 7:105-118.
• [40]Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodwars M, Marre M, Cooper M, Glasziou P, Grobbee D, Hamet P, Harrap S, Heller S, Liu L, Mancia G, Mogensen CE, Pan C, Poulter N, Rodger A, Williams B, Bompoint S, De Galan BE, Joshi R, Travert F: Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008, 358:2560-2572.
• [41]Duckworth W, Abraira C, Mortiz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG, Huang GD: Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009, 360:129-139.
• [42]Gerstein HC, Miller ME, RP B t, Goff DC Jr, Bigger JT, Buse JB, Cushman WC, Genuth S, Imail-Beigi F, Grimm RH Jr, Probstfield JL, Simons-Morton DG, Friedewald WT: Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008, 358:2545-2559.
• [43]Can A, Bekpinar S, Gurdol F, Tutuncu Y, Unlucerci Y, Dinccag N: Dimethylarginines in patients with type 2 diabetes mellitus: relation with the glycaemic control. Diabetes Res Clin Pract 2011, 94:e61-e64.
• [44]Yasuda S, Miyazaki S, Kanda M, Goto Y, Suzuki M, Harano Y, Nonogi H: Intensive treatment of risk factors in patients with type 2 diabetes mellitus is associated with improvement of endothelial function coupled with a reduction in the levels of plasma asymmetric dimethylarginine and endogenous inhibitor of nitric oxide synthase. Eur Heart J 2006, 27:1159-1165.
• [45]Kanazawa I, Yano S, Notsu Y, Yamaguchi T, Nabika T, Sugimoto T: Asymmetric dimethylarginine as a risk factor for cardiovascular disease in Japanese patients with type 2 diabetes mellitus. Clin Endocrinology 2011, 74:467-472.