Relationship of adiponectin and leptin to coronary artery disease, classical cardiovascular risk factors and atherothrombotic biomarkers in the IARS cohort

Jayashree Shanker; Veena S. Rao; Vandana Ravindran; Bhaskar Dhanalakshmi; Sridhara Hebbagodi; Vijay V. Kakkar

doi:10.1160/TH12-04-0263

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(04): 769-780
DOI: 10.1160/TH12-04-0263

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Relationship of adiponectin and leptin to coronary artery disease, classical cardiovascular risk factors and atherothrombotic biomarkers in the IARS cohort

Authors

Jayashree Shanker

¹Mary & Garry Weston Functional Genomics Unit, Thrombosis Research Institute India, Bangalore, India
Veena S. Rao

²Tata Proteomics & Coagulation Unit, Thrombosis Research Institute India, Bangalore, India
Vandana Ravindran

³Elizabeth & Emmanuel Kaye Bioinformatics and Statistics Unit, Thrombosis Research Institute India, Bangalore, India
Bhaskar Dhanalakshmi

⁴Clinical Research Unit, Thrombosis Research Institute India, Bangalore, India
Sridhara Hebbagodi

³Elizabeth & Emmanuel Kaye Bioinformatics and Statistics Unit, Thrombosis Research Institute India, Bangalore, India
Vijay V. Kakkar

⁵Scientific Chairman and Managing Trustee, Thrombosis Research Institute India, Bangalore, India

⁶President, Thrombosis Research Institute, London, UK

Abstract

Summary

Adiponectin and leptin link metabolic disorders and coronary artery disease (CAD). We analysed their relationship with CAD, classical risk factors and biomarkers in 287 CAD patients (cases) and 477 unaffected family members (controls) selected from the Indian Atherosclerosis Research Study (IARS). Classical risk factors included diabetes, hypertension, dyslipidaemia and obesity markers. Novel biomarkers were measured according to manufacturer recommendations. Adverse clinical events were recorded through telephonic follow-up. Cases showed lower adiponectin levels (4684.62 ± 190.73 ng/ml) than controls (5768.86 ± 152.87 ng/ml) (p=1.58X10^–5); Leptin levels were higher in affected males (12.47 ± 1.32 ng/ml) than in male controls (9.53 ± 1.19 ng/ml, p=0.017). Adiponectin 1^st quartile showed significant protection against CAD in females when compared to 3^rd (odds ratio [OR] 0.39, 0.16–0.92, p=0.032) or 4^th (OR 0.32, 0.14–0.72; p=0.006) quartile group. Leptin 3^rd quartile showed higher CAD risk in males as compared to 1^st quartile group (OR 2.09, 1.09–4.01, p=0.028). Subjects with metabolic syndrome showed low adiponectin and high leptin levels. Adipokines showed opposing association trend with lipids, inflammatory and coagulation markers and strong correlation (r=-0.14 to 0.52) with obesity markers. Cases with recurrent event and controls who developed new cardiac event during follow up showed high adiponectin levels (p<0.05). A model that combined adiponectin, leptin and conventional risk factors yielded the best ‘C’ index (0.890, 0.067–0.912). CAD patients in the top adiponectin tertile showed relatively poor survival curve as compared to the bottom Adiponectin tertile group. In conclusion, our findings strengthen the reported association between low adiponectin, high leptin, obesity-related metabolic disturbances and incident CAD in Asian Indians.

Keywords

Adiponectin - leptin - coronary artery disease - biomarkers - Asian Indians

Full Text

References

References
1 Szmitko PE, Teoh H, Stewart DJ. et al. Adiponectin and cardiovascular disease: state of the art?. Am J Physiol Heart Circ Physiol 2007; 292: H1655-1663.
2 Zyriax BC, Algenstaedt P, Hess UF. et al. Factors contributing to the risk of cardiovascular disease reflected by plasma adiponectin: data from the coronary risk factors for atherosclerosis in women (CORA) study. Atherosclerosis 2008; 200: 403-409.
3 Yamashita T, Matsuda M, Nishimoto O. et al. Combination of serum adiponectin level and metabolic syndrome is closely associated with coronary artery disease in Japanese subjects with good glycemic control. Intern Med 2010; 49: 721-727.
4 von Eynatten M, Hamann A, Twardella D. et al. Relationship of adiponectin with markers of systemic inflammation, atherogenic dyslipidemia, and heart failure in patients with coronary heart disease. Clin Chem 2006; 52: 853-859.
5 Teijeira-Fernandez E, Eiras S, Grigorian-Shamagian L. et al. Epicardial adipose tissue expression of adiponectin is lower in patients with hypertension. J Hum Hypertens 2008; 22: 856-863.
6 Iacobellis G, Sharma AM. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr Pharm Des 2007; 13: 2180-2184.
7 Sattar N, Wannamethee G, Sarwar N. et al. Adiponectin and coronary heart disease: a prospective study and meta-analysis. Circulation 2006; 114: 623-629.
8 Pilz S, Maerz W, Weihrauch G. et al. Adiponectin serum concentrations in men with coronary artery disease: the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. Clin Chim Acta 2006; 364: 251-255.
9 Pischon T, Girman CJ, Hotamisligil GS. et al. Plasma adiponectin levels and risk of myocardial infarction in men. J Am Med Assoc 2004; 291: 1730-1737.
10 Frystyk J, Berne C, Berglund L. et al. Serum adiponectin is a predictor of coronary heart disease: a population-based 10-year follow-up study in elderly men. J Clin Endocrinol Metab 2007; 92: 571-576.
11 Lau DC, Dhillon B, Yan H. et al. Adipokines: molecular links between obesity and atheroslcerosis. Am J Physiol Heart Circ Physiol 2005; 288: H2031-2041.
12 Sainani GS, Karatela RA. Plasma leptin in insulin-resistant and insulin-nonresistant coronary artery disease and its association with cardio-metabolic risk factors among Asian Indians. Metab Syndr Relat Disord 2009; 07: 335-340.
13 Ntyintyane L, Panz V, Raal FJ. et al. Leptin, adiponectin, and high-sensitivity C-reactive protein in relation to the metabolic syndrome in urban South African blacks with and without coronary artery disease. Metab Syndr Relat Disord 2009; 07: 243-248.
14 Martin SS, Qasim AN, Rader DJ. et al. C-Reactive Protein Modifies the Association of Plasma Leptin With Coronary Calcium in Asymptomatic Overweight Individuals. Obesity 2012; 20: 856-861.
15 Hou N, Luo JD. Leptin and cardiovascular diseases. Clin Exp Pharmacol Physiol 2011; 38: 905-913.
16 Al-Daghri N, Al-Rubean K, Bartlett WA. et al. Serum leptin is elevated in Saudi Arabian patients with metabolic syndrome and coronary artery disease. Diabet Med 2003; 20: 832-837.
17 Pilz S, Mangge H, Wellnitz B. et al. Adiponectin and mortality in patients undergoing coronary angiography. J Clin Endocrinol Metab 2006; 91: 4277-4286.
18 Nakamura Y, Shimada K, Fukuda D. et al. Implications of plasma concentrations of adiponectin in patients with coronary artery disease. Heart 2004; 90: 528-533.
19 Ku IA, Farzaneh-Far R, Vittinghoff E. et al. Association of low leptin with cardiovascular events and mortality in patients with stable coronary artery disease: the Heart and Soul Study. Atherosclerosis 2012; 217: 503-508.
20 Beatty AL, Zhang MH, Ku IA. et al. Adiponectin is associated with increased mortality and heart failure in patients with stable ischemic heart disease: data from the Heart and Soul Study. Atherosclerosis 2011; 220: 587-592.
21 Kantartzis K, Rittig K, Balletshofer B. et al. The relationships of plasma adiponectin with a favorable lipid profile, decreased inflammation, and less ectopic fat accumulation depend on adiposity. Clin Chem 2006; 52: 1934-1942.
22 Karatela RA, Sainani GS. Interrelationships of Factor VII activity and plasma leptin with insulin resistance in coronary heart disease. Atherosclerosis 2010; 209: 235-240.
23 El-Mesallamy HO, Hamdy NM, Salman TM. et al. Adiponectin and E-selectin concentrations in relation to inflammation in obese type 2 diabetic patients with coronary heart disease(s). Minerva Endocrinol 2011; 36: 163-170.
24 Bigalke B, Stellos K, Geisler T. et al. High plasma levels of adipocytokines are associated with platelet activation in patients with coronary artery disease. Platelets 2010; 21: 11-19.
25 Yokoyama H, Saito S, Daitoku K. et al. Effects of pravastatin and rosuvastatin on the generation of adiponectin in the visceral adipose tissue in patients with coronary artery disease. Fundam Clin Pharmacol 2011; 25: 378-387.
26 Saito S, Fujiwara T, Matsunaga T. et al. Increased adiponectin synthesis in the visceral adipose tissue in men with coronary artery disease treated with pravastatin: a role of the attenuation of oxidative stress. Atherosclerosis 2008; 199: 378-383.
27 Patel SR, Mailloux LM, Coppola JT. et al. Pioglitazone increases adiponectin levels in nondiabetic patients with coronary artery disease. Coron Artery Dis 2008; 19: 349-353.
28 Sakamoto K, Sakamoto T, Ogawa H. The effect of 6 months of treatment with pravastatin on serum adiponection concentrations in Japanese patients with coronary artery disease and hypercholesterolemia: a pilot study. Clin Ther 2006; 28: 1012-1021.
29 Krysiak R, Sierant M, Marek B. et al. The effect of angiotensin-converting enzyme inhibitors on plasma adipokine levels in normotensive patients with coronary artery disease. Endokrynol Pol 2010; 61: 280-287.
30 Gupta R, Joshi P, Mohan V. et al. Epidemiology and causation of coronary heart disease and stroke in India. Heart 2008; 94: 16-26.
31 Patel JV, Dwivedi S, Hughes EA. et al. Premature coronary artery disease: an inferred cardiovascular variant or a South Asian genetic disorder?. Thromb Haemost 2008; 99: 991-992.
32 Shanker J, Maitra A, Rao VS. et al. Rationale, design & preliminary findings of the Indian Atherosclerosis Research Study. Indian Heart J 2010; 62: 286-295.
33 Kumar NK. Bioethics activities in India. East Mediterr Health J 2006; 12 (Suppl. 01) S56-65.
34 Pencina MJ, D'Agostino Sr. RB, Demler OV. Novel metrics for evaluating improvement in discrimination: net reclassification and integrated discrimination improvement for normal variables and nested models. Stat Med 2012; 31: 101-113.
35 Ouchi N, Kihara S, Arita Y. et al. Novel modulator for endothelial adhesion molecules: adipocyte-derived plasma protein adiponectin. Circulation 1999; 100: 2473-2476.
36 Chen H, Montagnani M, Funahashi T. et al. Adiponectin stimulates production of nitric oxide in vascular endothelial cells. J Biol Chem 2003; 278: 45021-45026.
37 Kurata M, Okura T, Irita J. et al. The relationship between osteopontin and adiponectin in patients with essential hypertension. Clin Exp Hypertens 2010; 32: 358-363.
38 Li S, Shin HJ, Ding EL. et al. Adiponectin levels and risk of type 2 diabetes: a systematic review and meta-analysis. J Am Med Assoc 2009; 302: 179-188.
39 Mohan V, Deepa R, Pradeepa R. et al. Association of low adiponectin levels with the metabolic syndrome--the Chennai Urban Rural Epidemiology Study (CURES-4). Metabolism 2005; 54: 476-481.
40 Indulekha K, Anjana RM, Surendar J. et al. Association of visceral and subcutaneous fat with glucose intolerance, insulin resistance, adipocytokines and inflammatory markers in Asian Indians (CURES-113). Clin Biochem 2011; 44: 281-287.
41 Jurimae T, Jurimae J, Leppik A. et al. Relationships between adiponectin, leptin, and blood lipids in physically active postmenopausal females. Am J Hum Biol 2010; 22: 609-612.
42 Heslop CL, Frohlich JJ, Hill JS. Myeloperoxidase and C-reactive protein have combined utility for long-term prediction of cardiovascular mortality after coronary angiography. J Am Coll Cardiol 2010; 55: 1102-1109.
43 Mallat Z, Benessiano J, Simon T. et al. Circulating secretory phospholipase A2 activity and risk of incident coronary events in healthy men and women: the EPIC-Norfolk study. Arterioscler Thromb Vasc Biol 2007; 27: 1177-1183.
44 Maiolino G, Cesari M, Sticchi D. et al. Plasma adiponectin for prediction of cardiovascular events and mortality in high-risk patients. J Clin Endocrinol Metab 2008; 93: 3333-3340.
45 Huang SS, Huang PH, Chen YH. et al. Association of adiponectin with future cardiovascular events in patients after acute myocardial infarction. J Atheroscler Thromb 2010; 17: 295-303.
46 Lloyd-Jones DM, Liu K, Tian L. et al. Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease. Ann Intern Med 2006; 145: 35-42.
47 Greenland P, O'Malley PG. When is a new prediction marker useful? A consideration of lipoprotein-associated phospholipase A2 and C-reactive protein for stroke risk. Arch Intern Med 2005; 165: 2454-2456.
48 Cook NR. Use and misuse of the receiver operating characteristic curve in risk prediction. Circulation 2007; 115: 928-935.
49 Ho DY, Cook NR, Britton KA. et al. High-molecular-weight and total adiponectin levels and incident symptomatic peripheral artery disease in women: a prospective investigation. Circulation 2011; 124: 2303-2311.
50 Lara-Castro C, Luo N, Wallace P. et al. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006; 55: 249-259.
51 Skrabal CA, Czaja J, Honz K. et al. Adiponectin--its potential to predict and prevent coronary artery disease. Thorac Cardiovasc Surg 2011; 59: 201-206.
52 Hirata Y, Kurobe H, Akaike M. et al. Enhanced inflammation in epicardial fat in patients with coronary artery disease. Int Heart J 2011; 52: 139-142.
53 Pischon T, Hotamisligil GS, Rimm EB. Adiponectin: stability in plasma over 36 hours and within-person variation over 1 year. Clin Chem 2003; 49: 650-652.
54 Choi KM, Lee J, Lee KW. et al. Serum adiponectin concentrations predict the developments of type 2 diabetes and the metabolic syndrome in elderly Koreans. Clin Endocrinol (Oxf) 2004; 61: 75-80.
55 Hiuge-Shimizu A, Maeda N, Hirata A. et al. Dynamic changes of adiponectin and S100A8 levels by the selective peroxisome proliferator-activated receptor-gamma agonist rivoglitazone. Arterioscler Thromb Vasc Biol 2011; 31: 792-799.
56 Esposito K, Pontillo A, Di Palo C. et al. Effect of weight loss and lifestyle changes on vascular inflammatory markers in obese women: a randomized trial. J Am Med Assoc 2003; 289: 1799-1804.
57 Shetty S, Kusminski CM, Scherer PE. Adiponectin in health and disease: evaluation of adiponectin-targeted drug development strategies. Trends Pharmacol Sci 2009; 30: 234-239.

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