doi: 10.1161/01.CIR.0000082929.85234.E7
(Circulation. 2003;108:376.)
© 2003 American Heart Association, Inc.
Editorial |
Plasminogen Activator Inhibitor-1 and the Calculus of Mortality After Myocardial Infarction
From the Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, Tenn.
Correspondence to Douglas E. Vaughan, MD, Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Room 383 PRB, 2220 Pierce Ave, Nashville, TN 37232-6300. E-mail doug.vaughan{at}vanderbilt.edu
Key Words: Editorials • myocardial infarction • mortality
There are numerous clinical factors that have been identified that are associated with an adverse outcome after acute myocardial infarction (MI). These factors include female gender, the presence of severe left ventricular dysfunction or congestive heart failure, a history of diabetes mellitus, age >70 years, infarct location (anterior versus inferior), and patency of the infarct-related artery. In this issue of Circulation, Collet and colleagues1 describe a previously unrecognized relationship between acute increases in plasma levels of plasminogen activator inhibitor-1 (PAI-1) in patients hospitalized with acute ST-elevation MI and risk of mortality during a 1-month period.
See p 391
PAI-1 is the primary circulating inhibitor of tissue-type plasminogen activator and the urokinase-type plasminogen activator in plasma. Elevated plasma PAI-1 levels have been shown to be a predictor of recurrent MI2 and have been identified as an independent predictor of cardiovascular risk.3 When one considers the many factors that regulate plasma PAI-1 levels, it is not completely surprising that acute increases in the levels of PAI-1 in plasma might reflect increased risk of mortality after acute MI. The PAI-1 that circulates in plasma is derived from the composite output of several different cellular synthetic sites, including the liver, the vascular endothelium, and visceral adipose tissue. There are a number of factors that are known to directly affect PAI-1 production, including metabolic factors such as glucose,4 insulin,5 and VLDL,6 neurohumoral factors including angiotensin II and aldosterone,7,8 and inflammatory cytokines including tumor necrosis factor-
9 and interleukin-1.10 The remarkable relationship described in this study could reflect the impact of any or all of the previously listed mechanisms. For example, it has been shown previously that impaired glucose control is an independent predictor of risk after acute MI.11 Although the level of metabolic control in this population is not described, it certainly is possible that some of the mortality associated with elevated PAI-1 levels reported here may simply reflect poor glycemic control in the peri-infarct setting. PAI-1 is commonly and predictably elevated in individuals with insulin resistance and type II diabetes, and whereas diabetics made up 
19% of the population studied here, it is not clear whether they were overrepresented with regard to 1-month mortality.
Our group and others have shown a strong relationship between activation of the renin-angiotensin-aldosterone system (RAAS) and plasma PAI-1.12,13 It is known that the RAAS is activated after acute MI.14 The level of activation of the RAAS can also reflect the extent and severity of left ventricular dysfunction after acute anterior MI.15 In this context, PAI-1 may represent a circulating marker of activation of the RAAS that may be indirectly related to infarct size. PAI-1 is also a classic acute phase reactant and is strongly upregulated by inflammatory cytokines. Healing after MI involves an inflammatory process that is generally thought to occur later in the course of events after an MI, a process temporally delayed from the early increase in PAI-1 seen in this study, although some inflammatory contribution to these acute increases cannot be excluded.
There are several important limitations to this study. The population examined is relatively small in size, which precludes any definitive conclusions being drawn at present. The novelty of the associations suggests that these observations deserve to be validated in larger and better-characterized populations. Although the authors were successful in identifying a change in plasma PAI-1 as a predictor of risk, it is surprising that the well-known circadian variation patterns in plasma PAI-116 did not confound the results or diminish the differences between subjects who survived and those who died. There is also no accompanying information on the potential benefit of therapies, both pharmacological and nonpharmacological, that might prevent the acute increase in plasma PAI-1. These potentially include ACE inhibitors,17 insulin synthesizing agents,18 or other agents that improve endothelial function and nitric oxide production systematically.
Overall, this study suggests that the acute release of PAI-1 in ST-elevation MI helps identify patients at risk for undesirable outcomes. The novelty and statistical strength of the association reported are noteworthy and should provide a strong impetus for further investigation. It is tempting to speculate that additional therapeutic measures that reduce PAI-1 production or directly antagonize PAI-1 activity may eventually be of value in the setting of acute MI.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
References
1. Collet JP, Montalescot G, Vicaut E, et al. Acute release of plasminogen activator inhibitor-1 in ST-segment elevation myocardial infarction predicts mortality. Circulation. 2003; 108: 391–394.
2. Hamsten A, de Faire U, Walldius G, et al. Plasminogen activator inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet. 1987; 2: 3–9.[CrossRef][Medline] [Order article via Infotrieve]
3. Thogersen AM, Jansson JH, Boman K, et al. High plasminogen activator inhibitor and tissue plasminogen activator levels in plasma precede a first acute myocardial infarction in both men and women: evidence for the fibrinolytic system as an independent primary risk factor. Circulation. 1998; 98: 2241–2247.
4. Nordt TK, Klassen KJ, Schneider DJ, et al. Augmentation of synthesis of plasminogen activator inhibitor type-1 in arterial endothelial cells by glucose and its implications for local fibrinolysis. Arterioscler Thromb. 1993; 13: 1822–1828.
5. Nordt TK, Sawa H, Fujii S, et al. Induction of plasminogen activator inhibitor type-1 (PAI-1) by proinsulin and insulin in vivo. Circulation. 1995; 91: 764–770.
6. Eriksson P, Nilsson L, Karpe F, et al. Very-low-density lipoprotein response element in the promoter region of the human plasminogen activator inhibitor-1 gene implicated in the impaired fibrinolysis of hypertriglyceridemia. Arterioscler Thromb Vasc Biol. 1998; 18: 20–26.
7. Vaughan DE, Lazos SA, Tong K. Angiotensin II regulates the expression of plasminogen activator inhibitor-1 in cultured endothelial cells: a potential link between the renin-angiotensin system and thrombosis. J Clin Invest. 1995; 95: 995–1001.[Medline] [Order article via Infotrieve]
8. Brown NJ, Kim KS, Chen YQ, et al. Synergistic effect of adrenal steroids and angiotensin II on plasminogen activator inhibitor-1 production. J Clin Endocrinol Metab. 2000; 85: 336–344.
9. Sawdey MS, Loskutoff DJ. Regulation of murine type 1 plasminogen activator inhibitor gene expression in vivo: tissue specificity and induction by lipopolysaccharide, tumor necrosis factor-alpha, and transforming growth factor-beta. J Clin Invest. 1991; 88: 1346–1353.[Medline] [Order article via Infotrieve]
10. Bevilacqua MP, Schleef RR, Gimbrone MA Jr, et al. Regulation of the fibrinolytic system of cultured human vascular endothelium by interleukin 1. J Clin Invest. 1986; 78: 587–591.[Medline] [Order article via Infotrieve]
11. Malmberg K, Ryden L, Efendic S, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI study): effects on mortality at 1 year. J Am Coll Cardiol. 1995; 26: 57–65.[Abstract]
12. Brown NJ, Gainer JV, Stein CM, et al. Effect of activation and inhibition of the renin-angiotensin system on plasma PAI-1. Hypertension. 1998; 32: 965–971.
13. Brown NJ, Agirbasli M, Vaughan DE. Comparative effect of angiotensin-converting enzyme inhibition and angiotensin II type 1 receptor antagonism on plasma fibrinolytic balance in humans. Hypertension. 1999; 34: 285–290.
14. Rouleau JL, Moye LA, de Champlain J, et al. Activation of neurohumoral systems following acute myocardial infarction. Am J Cardiol. 1991; 68: 80D–86D.[CrossRef][Medline] [Order article via Infotrieve]
15. Vaughan DE, Lamas GA, Pfeffer MA. Role of left ventricular dysfunction in selective neurohumoral activation in the recovery phase of anterior wall acute myocardial infarction. Am J Cardiol. 1990; 66: 529–532.[CrossRef][Medline] [Order article via Infotrieve]
16. Andreotti F, Kluft C. Circadian variation of fibrinolytic activity in blood. Chronobiol Int. 1991; 8: 336–351.[Medline] [Order article via Infotrieve]
17. Vaughan DE, Rouleau J-L, Ridker PM, et al. Effects of ramipril on plasma fibrinolytic balance in patients with acute anterior myocardial infarction. Circulation. 1997; 96: 442–447.
18. Vague P, Juhan-Vague I, Alessi MC, et al. Metformin decreases the high plasminogen activator inhibition capacity, plasma insulin and triglyceride levels in non-diabetic obese subjects. Thromb Haemost. 1987; 57: 326–328.[Medline] [Order article via Infotrieve]
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Circulation 2003 108: 391-394.
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