Pregnancy-associated plasma protein a as predictor of outcome in patients with suspected acute coronary syndromes.

Predictor of Outcome in Patients With Suspected Acute Coronary Syndromes We read with interest the article by Lund et al1 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 2.9 mIU/L, adjusted for C-reactive protein (CRP), age, gender, diabetes, current smoking, hypertension, previous myocardial infarction, and congestive heart failure was superior to that of CRP 2 mg/L: 4.6 for PAPP-A (95% confidence interval 1.8 to 11.8, P 0.002) versus 2.6 for CRP (95% confidence interval 1.1 to 6.5, P 0.03). The cumulative risk of an event, graded by increasing PAPP-A values, was 8% in the lowest group and 37.9% in the highest (P 0.0012). PAPP-A and CRP levels were independent of each other (r 0.03, P 0.7 on admission; r 0.02, P 0.8 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 enzymes1 and inflammatory markers. The remission of rheumatoid arthritis and other inflammatory states during pregnancy5 (the prototype of increased PAPP-A) denotes PAPP-A as a suppressor, rather than mediator, of inflammation and tissue damage.