Prospective evaluation of pregnancy-associated plasma protein-a and outcomes in patients with acute coronary syndromes.
OBJECTIVE
This study sought to investigate whether pregnancy-associated plasma protein-A (PAPP-A) is useful for risk assessment in non-ST-segment elevation acute coronary syndrome (NSTE-ACS).


BACKGROUND
PAPP-A is a high molecular weight, zinc-binding metalloproteinase that is associated with vulnerable plaque and may be a predictor of cardiovascular disease and mortality.


METHODS
We measured PAPP-A at baseline in 3,782 patients with non NSTE-ACS randomized to ranolazine or placebo in the MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes) trial and followed for an average of 1 year. A cut point of 6.0 μIU/ml was chosen from pilot work in this cohort.


RESULTS
PAPP-A >6.0 μIU/ml at presentation was associated with higher rates of cardiovascular death (CVD) or myocardial infarction (MI) at 30 days (7.4% vs. 3.7%, hazard ratio [HR]: 2.01; 95% confidence interval [CI]: 1.43 to 2.82; p < 0.001) and at 1 year (14.9% vs. 9.7%, HR: 1.63; 95% CI: 1.29 to 2.05; p < 0.001). PAPP-A was also associated with higher rates of CVD (HR: 1.94; 95% CI: 1.07 to 3.52, p = 0.027) and myocardial infarction (HR: 1.82; 95% CI: 1.22 to 2.71, p = 0.003) individually at 30 days. There was no difference in the risk associated with PAPP-A stratified by baseline cardiac troponin I [Accu-TnI >0.04 μg/l], p interaction = 0.87). After adjustment for cardiac troponin I, ST-segment deviation, age, sex, diabetes, smoking, hypertension, and coronary artery disease, PAPP-A was independently associated with CVD/myocardial infarction at 30 days (adjusted HR: 1.62, 95% CI: 1.15 to 2.29; p = 0.006) and 1 year (adjusted HR: 1.35, 95% CI: 1.07 to 1.71; p = 0.012). PAPP-A also improved the net reclassification for CVD/MI (p = 0.003). There was no significant interaction with ranolazine.


CONCLUSIONS
PAPP-A was independently associated with recurrent cardiovascular events in patients with NSTE-ACS. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications.
Brigham and Women's Hospital, Boston, Massachusetts, USA. mbonaca@partners.org
Marc P
MP
Bonaca
Benjamin M
BM
Scirica
Marc S
MS
Sabatine
Petr
P
Jarolim
Sabina A
SA
Murphy
Janna S
JS
Chamberlin
Daniel W
DW
Rhodes
Paula C
PC
Southwick
Eugene
E
Braunwald
David A
DA
Morrow
D000083:Acetanilides / Q000009:adverse effects / Q000627:therapeutic use*; D054058:Acute Coronary Syndrome / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D002423:Cause of Death; D004562:Electrocardiography; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009203:Myocardial Infarction / Q000097:blood* / Q000188:drug therapy* / Q000401:mortality; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011247:Pregnancy; D011266:Pregnancy-Associated Plasma Protein-A / Q000378:metabolism*; D011379:Prognosis; D011446:Prospective Studies; D000069458:Ranolazine; D012008:Recurrence; D018570:Risk Assessment; D012815:Signal Processing, Computer-Assisted; D016019:Survival Analysis; D014336:Troponin / Q000097:blood
D000083:Acetanilides; D015415:Biomarkers; D004791:Enzyme Inhibitors; D010879:Piperazines; D014336:Troponin; D000069458:Ranolazine; D011266:Pregnancy-Associated Plasma Protein-A