(Stroke. 2005;36:1919.)
© 2005 American Heart Association, Inc.
Editorial Comment |
Adiponectin
Spectator or Player?
Oregon Stroke Center, Oregon Health Sciences University, Portland, Oregon
Key Words: inflammation • risk factors
Despite efforts at controlling traditional risk factors, stroke remains a devastating and all-too-common disease. Identifying new markers for patients at higher risk of stroke would aid in future risk factor management as well as potentially offering new venues for preventive therapies. In this issue of Stroke, Efstathiou et al1 report on a highly significant inverse relation between adiponectin levels and subsequent 5-year mortality. Adiponectin, a recently discovered cytokine, has previously been theorized to be involved in the development of atherosclerotic disease.2 Adiponectin appears to have both anti-inflammatory and antiatherogenic properties, and as such, it was expected that there would be an inverse relation between the serum level of adiponectin and subsequent cerebrovascular mortality. In their study, Efstathiou et al confirm this inverse relation, finding that patients with adiponectin levels in the lowest tertile had a 92.8% 5-year mortality compared with a 10.5% mortality in patients with adiponectin levels in the highest tertile.1 This corresponds to an 8-fold increase in risk for individuals with low adiponectin levels compared with those with the highest tertile of adiponectin levels. Similar results with adiponectin have been seen in cardiovascular disease. In a case-control analysis from the Health Professionals Follow-up Study, among the 18 225 men without cardiovascular disease at baseline, those in the highest quintile of adiponectin level had a significantly reduced risk for myocardial infarction (relative risk [RR], 0.39; 95% confidence interval, 0.23 to 0.64; P for trend <0.001) compared with in the lowest quintile of adiponectin level.3
The results of this study support the role of cytokines in stroke4 and are consistent with prior studies suggesting that a persistent inflammatory response increases the risk of subsequent cerebrovascular disease. The first group to demonstrate a persistent inflammatory response was Beamer et al, 5 who found that fibrinogen, C-reactive protein (CRP), and white blood cell levels at baseline were predictive of recurrent vascular events at 1 year. They also found that fibrinogen remained significantly elevated at 1 year and that it continued to predict an increased risk for recurrent vascular events. However, the magnitude of the ability of fibrinogen to predict recurrent events was much less than that seen in the current apidonectin study. Other markers of the inflammatory response, including interleukin (IL)-6 and CRP, did not independently predict recurrent events in their study.
In addition to fibrinogen, some of the other inflammatory markers that have been linked to recurrent cardiac or stroke events include CRP (RR, 4),6 lipoprotein-associated phospholipase A2 (relative risk, 1.5),7 IL-6 (RR, 2),8 and cell adhesion molecules such as soluble intercellular adhesion molecule-1 (RR, 3).9 These compare to the 8-fold increased RR seen in the current study. However, it should be noted that all of these results were based on studies involving thousands of patients compared with the 160 studied by Efstathiou et al.
The current study found that apidonectin levels were low-normal after acute stroke. Prior studies found that the anti-inflammatory cytokines IL-6 and IL-1RA increase acutely after stroke,10 implying that there is activation of anti-inflammatory components. The finding that apidonectin did not increase acutely suggests that although apidonectin may be protective, there may be no mechanisms to quickly upregulate it, at least shortly after stroke.
In the current study, apidonectin appears to be both potentially a marker of the extent of underlying neurologic injury and a marker of persistent inflammatory response. That apidonectin is in part a marker for the extent of neurologic injury is supported by the negative correlation between initial infarct volume and apidonectin, as well as the inverse relation between the National Institutes of Health Stroke Scale and apidonectin levels. However, the authors also provide data supporting the theory that apidonectin is involved in a chronic anti-inflammatory response; in the 71 patients tested at 1 year, apidonectin levels remained nearly the same as they had at baseline. In addition, patients tended to be in the same apidonectin tertile group to which they were initially stratified. The authors also found a significant negative correlation with apidonectin and CRP (P=0.004); however, they did not provide information as to whether CRP was as powerful a predictor of 5-year mortality as the apidonectin level was. In addition, although CRP remained elevated compared with normal in the 71 patients assessed at 1 year, it was more likely to have declined from the initial baseline value compared with an apidonectin level that had shown very little change from baseline. This suggests that CRP is relatively more reflective of an acute-phase reaction, whereas apidonectin is more representative of the underlying chronic inflammatory state of the patient.
What this article does not tell us is whether apidonectin is merely a marker of a persistent inflammatory response or whether it has anti-inflammatory properties. There are some limited data that apidonectin may have some direct insulin-sensitizing and anti-inflammatory properties.2 The only way of proving this in cerebrovascular cases would be to design a therapeutic trial that targets elevating apidonectin levels in patients at risk for stroke. The first step in designing such a therapeutic trial would be to discover an agent that reliably elevates apidonectin levels. In the discussion section, the authors reviewed several medications that have variable effects on raising apidonectin levels. It appears that further work confirming an effective apidonectin-elevating therapy is indicated.
The results of this study support the theory that inflammation is involved in recurrent stroke and mortality. At the very least, apidonectin appears to be a robust marker of subsequent vascular events. However, it could also provide fertile ground for potential therapeutic trials that target increasing apidonectin.
References
- Efstathiou SP, Tsioulos DI, Tsiakou AG, Gratsias YE, Pefanis AV, Mountokalakis TD. Plasma adiponectin levels and 5-year survival after first-ever ischemic stroke. Stroke. 2005; 36: 1915–1919.
[Abstract/Free Full Text] - Goldstein BJ, Scalia R. Adiponectin: a novel adipokine linking adipocytes and vascular functioin. J Clin Endocrinol Metab. 2004; 89: 2563–2568.
[Abstract/Free Full Text] - Pischon CJ, Girman GS, Hotamisligil GS. Plasma apidonectin levels and risk of myocardial infarction in men. JAMA. 2004; 291: 1730–1737.
[Abstract/Free Full Text] - Clark WM. Cytokines and reperfusion injury. Neurology. 1997; 49 (suppl 4): S10–S14.[Medline] [Order article via Infotrieve]
- Beamer NB, Coull BM, Clark WM, Briley DP, Wynn M, Sexton G. Persistent inflammatory response in stroke survivors. Neurology. 1998; 50: 1722–1728.[Abstract]
- Bassuk SS, Rifai N, Riker PM. High-sensitivity C-reactive protein: clinical importance. Curr Probl Cardiol. 2004; 29: 439–493.[Medline] [Order article via Infotrieve]
- Packard CJ, O’Reilly DS, Caslake MJ. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease: West of Scotland Coronary Prevention Study Group. N Engl J Med. 2000; 343: 1148–1155.
[Abstract/Free Full Text] - Ridker PM, Rifai N, Stampfer MJ, Hennekens CH. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation. 2000; 101: 1767–1772.
[Abstract/Free Full Text] - Ridker PM, Hennekens CH, Roitman-Johnson B, Stamfer MJ, et al. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet. 1998; 351: 88–92.[CrossRef][Medline] [Order article via Infotrieve]
- Beamer NB, Coull BM, Clark WM, Hazel JS, Silberger JR. Interleukin-6 and interleukin-1 receptor antagonist in acute stroke. Ann Neurol. 1995; 6: 801–805.
Related Article:
- Plasma Adiponectin Levels and Five-Year Survival After First-Ever Ischemic Stroke
- Stamatis P. Efstathiou, Dimitrios I. Tsioulos, Aphrodite G. Tsiakou, Yannis E. Gratsias, Angelos V. Pefanis, and Theodore D. Mountokalakis
Stroke 2005 36: 1915-1919.[Abstract] [Full Text] [PDF]
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