Perindopril treatment promote left ventricle remodeling in patients with heart failure screened positive for autoantibodies against angiotensin II type 1 receptor

BMC Cardiovascular Disorders

Lin Zhang²  Aihua Hu¹  Hakon Hakonarson¹  Jin Chen²  Juan Zhang²  Jiamei Liu²  Zhiyong Zhang²  Lin Xu²  Xin Wang²  Hua Wang²  Jinling Wu²  Qian Du² 

[1]Children's Hospital of Philadelphia Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

[2]Heart Failure Center, Departments of Cardiology, Capital Medical University, Chao-Yang Hospital, Beijing, China

关键词: Biomarker;    Renin-angiotensin-aldosterone system;    Anti-AT₁-AR;   

Others  :  856726
DOI  :  10.1186/1471-2261-13-94

 received in 2012-12-16, accepted in 2013-10-25,  发布年份 2013

【 摘 要 】

Background

Autoantibodies specific to the angiotensin II type I receptor (anti-AT₁-AR) have been implicated in the pathology of congestive heart failure (CHF). Anti-AT₁-AR may be associated with left ventricular function in CHF patients treated with perindopril.

Methods

Synthetic angiotensin II type 1 receptor (AT₁-R) peptides served as the target antigen. ELISA was used to screen the sera of 156 CHF patients, which were divided into positive and negative groups based on their anti-AT₁-AR reactivity. Echocardiography and a 6-minute walk test were performed at baseline and after one year of perindopril therapy. The end-point events were compared over a 5-year follow-up.

Results

Final analysis covered 138 patients, including 82 positive and 56 negative. The frequency and geometric mean titre of anti-AT₁-AR were significantly lower in the positive group after one year of treatment (all P < 0.01, from 100% to 73.2% and from 1:125.3 ± 1.0 to 1:69.2 ± 1.1). Of these, 22 patients showed no antibodies. Both groups showed improvement in left ventricular end-diastole, end-systolic dimensions, ejection fraction, and a 6-minute walk test by perindopril in combination with standard treatment regime for one year (all P < 0.01). However, the 82 patients positive for anti-AT₁-AR showed more pronounced improvement than the 56 negative patients (all P < 0.05). However, after 5 years of follow-up, the rate of all causes and cardiovascular mortality attributable to any cause and the re-hospitalisation rate showed no significant differences between the two groups (all P > 0.05).

Conclusions

Perindopril treatment significantly decreased the frequency and geometric mean titre in patients positive for anti-AT₁-AR, even to complete ablation. These patients showed greater improvement in left ventricular remodeling and heart function than negative that in patients after one year of perindopril treatment in combination with standard treatment, but no significant differences in endpoint events were observed in the following 5 years. Anti-AT₁-AR might be a useful biomarker of over-activation of the renin-angiotensin-aldosterone system for clinical medication.

【 授权许可】

   
2013 Du et al.; licensee BioMed Central Ltd.

【 图 表 】

【 参考文献 】

• [1]Wallukat G, Homuth V, Jupner A, Ruckert E, Haller H, Luft FC: Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT(1) receptor. Hypertension 1997, 30(4):123-123.
• [2]Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jupner A, Baur E, Nissen E, Vetter K, Neichel D, et al.: Patients with preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 1999, 103(7):945-952.
• [3]Jin Z, Wang J, Zhang WH, Zhang GH, Jiao XY, Zhi JM: Changes in cardiac structure and function in rats immunized by angiotensin type 1 receptor peptides. Acta Biochim Biophys Sin (Shanghai) 2011, 43(12):970-976.
• [4]Wallukat G, Neichel D, Nissen E, Homuth V, Luft FC: Agonistic autoantibodies directed against the angiotensin II AT1 receptor in patients with preeclampsia. Can J Physiol Pharmacol 2003, 81(2):79-83.
• [5]Vantrimpont P, Rouleau JL, Wun CC, Ciampi A, Klein M, Sussex B, Arnold JM, Moye L, Pfeffer M: Additive beneficial effects of beta-blockers to angiotensin-converting enzyme inhibitors in the Survival and Ventricular Enlargement (SAVE) Study. SAVE Investigators. J Am Coll Cardiol 1997, 29(2):229-236.
• [6]Atlas SA: The renin-angiotensin aldosterone system: pathophysiological role and pharmacologic inhibition. J Manag Care Pharm 2007, 13(8 Suppl B):9-20.
• [7]Enright PL: The six-minute walk test. Respir Care 2003, 48(8):783-785.
• [8]Fu ML, Herlitz H, Schulze W, Wallukat G, Micke P, Eftekhari P, Sjogren KG, Hjalmarson A, Muller-Esterl W, Hoebeke J: Autoantibodies against the angiotensin receptor (AT1) in patients with hypertension. J Hypertens 2000, 18(7):945-953.
• [9]Ma G, Li Y, Zhang J, Liu H, Hou D, Zhu L, Zhang Z, Zhang L: Association between the presence of autoantibodies against adrenoreceptors and severe pre-eclampsia: a pilot study. PLoS One 2013, 8(3):e57983.
• [10]Zou C, Zhang Z, Zhao W, Li G, Ma G, Yang X, Zhang J, Zhang L: Predictive value of pre-procedural autoantibodies against M2-muscarinic acetylcholine receptor for recurrence of atrial fibrillation one year after radiofrequency catheter ablation. J Transl Med 2013, 11:7. BioMed Central Full Text
• [11]Liao YH, Wei YM, Wang M, Wang ZH, Yuan HT, Cheng LX: Autoantibodies against AT1-receptor and alpha1-adrenergic receptor in patients with hypertension. Hypertension research 2002, 25(4):641-646.
• [12]Voors AA, van Veldhuisen DJ: Pharmacological treatment of chronic heart failure according to the 2005 guidelines of the European Society of Cardiology. Minerva cardioangiologica 2005, 53(4):233-239.
• [13]Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, et al.: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 2005, 112(12):e154-e235.
• [14]Chabot A, Jiang BH, Shi Y, Tardif JC, Dupuis J: Role of aldosterone on lung structural remodeling and right ventricular function in congestive heart failure. BMC Cardiovasc Disord 2011, 11:72. BioMed Central Full Text
• [15]Zhang L, Cui L, Miao GB, Zhao WS, Wang SY, Liu XL: [Study of autoantibodies against the G-protein-coupled beta 2- and alpha 1-adrenergic and AT1 receptors in patients with primary hypertension]. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2002, 24(4):367-369.
• [16]Tepper D: A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. Congest Heart Fail 2002, 8(1):57-58.
• [17]Fazeli G, Stopper H, Schinzel R, Ni CW, Jo H, Schupp N: Angiotensin II induces DNA damage via AT1 receptor and NADPH oxidase isoform Nox4. Mutagenesis 2012, 27(6):673-681.
• [18]Yoshida H, Takahashi M, Tanonaka K, Maki T, Nasa Y, Takeo S: Effects of ACE inhibition and angiotensin II type 1 receptor blockade on cardiac function and G proteins in rats with chronic heart failure. Br J Pharmacol 2001, 134(1):150-160.
• [19]LaMarca B, Wallace K, Granger J: Role of angiotensin II type I receptor agonistic autoantibodies (AT1-AA) in preeclampsia. Curr Opin Pharmacol 2011, 11(2):175-179.
• [20]Dragun D, Muller DN, Brasen JH, Fritsche L, Nieminen-Kelha M, Dechend R, Kintscher U, Rudolph B, Hoebeke J, Eckert D, et al.: Angiotensin II type 1-receptor activating antibodies in renal-allograft rejection. N Engl J Med 2005, 352(6):558-569.
• [21]Dechend R, Viedt C, Muller DN, Ugele B, Brandes RP, Wallukat G, Park JK, Janke J, Barta P, Theuer J, et al.: AT1 receptor agonistic antibodies from preeclamptic patients stimulate NADPH oxidase. Circulation 2003, 107(12):1632-1639.
• [22]Chai W, Zhang W, Jin Z, Feng Y, Kuang Y, Zhi J: Angiotensin II type I receptor agonistic autoantibody-induced apoptosis in neonatal rat cardiomyocytes is dependent on the generation of tumor necrosis factor-alpha. Acta Biochim Biophys Sin (Shanghai) 2012, 44(12):984-990.
• [23]Zhang S, Zhang X, Yang L, Yan Z, Yan L, Tian J, Li X, Song L, Wang L, Yang X, et al.: Increased susceptibility to metabolic syndrome in adult offspring of angiotensin type 1 receptor autoantibody-positive rats. Antioxid Redox Signal 2012, 17(5):733-743.
• [24]Cappuzzello C, Di Vito L, Melchionna R, Melillo G, Silvestri L, Cesareo E, Crea F, Liuzzo G, Facchiano A, Capogrossi MC, et al.: Increase of plasma IL-9 and decrease of plasma IL-5, IL-7, and IFN-gamma in patients with chronic heart failure. J Transl Med 2011, 9:28. BioMed Central Full Text
• [25]Lanfear DE, Hasan R, Gupta RC, Williams C, Czerska B, Tita C, Bazari R, Sabbah HN: Short term effects of milrinone on biomarkers of necrosis, apoptosis, and inflammation in patients with severe heart failure. J Transl Med 2009, 7:67. BioMed Central Full Text
• [26]McMurray J, Davie AP: Angiotensin-(1–7) attenuates the development of heart failure after myocardial infarction in rats. Circulation 2002, 106(20):e147. author reply e147
• [27]Chappell MC: Emerging evidence for a functional angiotensin-converting enzyme 2-angiotensin-(1–7)-MAS receptor axis: more than regulation of blood pressure? Hypertension 2007, 50(4):596-599.
• [28]Thai H, Wollmuth J, Goldman S, Gaballa M: Angiotensin subtype 1 rReceptor (AT1) blockade improves vasorelaxation in heart failure by up-regulation of endothelial nitric-oxide synthase via activation of the AT2 receptor. J Pharmacol Exp Ther 2003, 307(3):1171-1178.
• [29]Gao L, Zucker IH: AT2 receptor signaling and sympathetic regulation. Curr Opin Pharmacol 2011, 11(2):124-130.
• [30]Rossitto G, Regolisti G, Rossi E, Negro A, Nicoli D, Casali B, Toniato A, Caroccia B, Seccia TM, Walther T, et al.: Elevation of angiotensin-II type-1-receptor autoantibodies titer in primary aldosteronism as a result of aldosterone-producing adenoma. Hypertension 2013, 61(2):526-533.
• [31]Stork S, Boivin V, Horf R, Hein L, Lohse MJ, Angermann CE, Jahns R: Stimulating autoantibodies directed against the cardiac beta1-adrenergic receptor predict increased mortality in idiopathic cardiomyopathy. Am Heart J 2006, 152(4):697-704.
• [32]Zannad F, Agrinier N, Alla F: Heart failure burden and therapy. Europace 2009, 11(Suppl 5):v1-v9.