We read with interest the article by Lund et al 1 on circulating pregnancy-associated plasma protein A (PAPP-A) in 136 patients evaluated for suspected acute coronary syndrome without cardiac troponin I elevation. PAPP-A concentrations above 2.9 mIU/L during the first 24 hours independently predicted cardiovascular death, nonfatal myocardial infarction, or revascularization over the following 6 months. The risk ratio of PAPP-A Ͼ2.9 mIU/L, adjusted for C-reactive protein (CRP), age, gender,

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... tes, current smoking, hypertension, previous myocardial infarction, and congestive heart failure was superior to that of CRP Ͼ2 mg/L: 4.6 for PAPP-A (95% confidence interval 1.8 to 11.8, Pϭ0.002) versus 2.6 for CRP (95% confidence interval 1.1 to 6.5, Pϭ0.03). The cumulative risk of an event, graded by increasing PAPP-A values, was 8% in the lowest group and 37.9% in the highest (Pϭ0.0012). PAPP-A and CRP levels were independent of each other (rϭϪ0.03, Pϭ0.7 on admission; rϭ0.02, Pϭ0.8 for peak values). These striking data are discussed only briefly by the authors, who, despite showing a lack of correlation between PAPP-A and CRP, propose PAPP-A as a mediator of the inflammatory reactions that would lead to plaque rupture and clinical instability. We would like to propose an alternative interpretation, based on the main activity of PAPP-A, which is to cleave insulin-like growth factor-1 (IGF-1) from its binding protein-4, thereby increasing the accessibility of free IGF-1 to tissues. 2 Several lines of evidence indicate that PAPP-A is induced in response to, and within, damaged tissues, as a promoter of repair, in virtue of its IGF-1-dependent actions on vasculogenesis, vasodilation, cell preconditioning, cell survival, and insulin-sensitivity. 3,4 Even mild damage, such as brief ischemia, would activate this pathway, 2 thus explaining the higher sensitivity of PAPP-A compared with cardiac troponins as predictors of outcome. In response to necrosis, the broad-ranging fluctuations of PAPP-A justify its correlation with cardiac enzymes 1 and inflammatory markers. The remission of rheumatoid arthritis and other inflammatory states during pregnancy 5 (the prototype of increased PAPP-A) denotes PAPP-A as a suppressor, rather than mediator, of inflammation and tissue damage.