Prospective Evaluation of Pregnancy-Associated Plasma Protein-A and Outcomes in Patients With Acute Coronary Syndromes

Editor's Note: Based on Bonaca MP, Scirica BM, Sabatine MS, Jarolim P, et al. Prospective evaluation of pregnancy-associated plasma protein-a and outcomes in patients with acute coronary syndromes. J Am Coll Cardiol 2012;60(4):332-8.

Article Summary

Background: Metalloproteinases have been implicated in the destabilization of atherosclerotic plaque, specifically, degrading the proteins that maintain the integrity of the protective fibrous cap. Pregnancy-associated plasma protein-A (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. 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).

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 who were followed for an average of 1 year. A cut point of 6.0 IU/ml was chosen from pilot work in this cohort.

Results: PAPP-A 6.0 IU/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 when patients were 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). Moreover, when inflammatory markers (CRP and myeloperoxidase) and BNP were added to the model in addition to TnI, only PAPP-A remained a predictor of CV death or MI at 30 days (adjusted HR: 1.56; 95% CI: 1.09 to 2.24; p=0.015) and 1 year (adjusted HR: 1.37; 95% CI: 1.07 to 1.75; p = 0.011). PAPP-A improved the net reclassification for CVD/MI (p=0.003). There was no significant interaction with ranolazine. There was no significant interaction between PAPP-A and heparin use for CV death/MI or CV death, MI, or severe recurrent ischemia at 30 days or 1 year (p>0.65 for each interaction).

Conclusion: PAPP-A was independently associated with the short- and long-term risk of cardiovascular death and recurrent ischemic events in patients with NSTE-ACS, along with clinical predictors and cTnI. This finding supports PAPP-A as a candidate prognostic marker in patients with ACS and supports investigation of its therapeutic implications.

Commentary/Perspective: Our study prospectively demonstrated a significant relationship between PAPP-A and cardiovascular death or recurrent ischemic events in 3,782 patients presenting with NSTE-ACS.

A number of candidate biomarkers have shown potential prognostic value in patients with ACS, particularly for the endpoints of mortality, heart failure as well as broad composite endpoints. The observation that PAPP-A was associated specifically with recurrent ischemic events rather than heart failure is important in that few markers have demonstrated prognostic value for this endpoint independent of current generation sensitive troponin assays. In addition, these findings are consistent with the hypothesized role of PAPP-A in the destabilization of atherosclerotic plaque. In our study there was a weak correlation between PAPP-A and markers of myonecrosis, hemodynamic stress, and other nonspecific markers of inflammation supporting the hypothesis that this metalloproteinase reflects a distinct pathway underlying the development of recurrent ischemic events.

Overall these findings support PAPP-A as a candidate prognostic marker of recurrent ischemia and cardiovascular death in patients with NSTE-ACS. Importantly, these findings also support additional mechanistic investigation of possible pathways through which PAPP-A may play a role in the pathobiology of ACS. Further investigations are likely to be valuable in elucidating the potential for PAPP-A as a therapeutic target.


  1. Libby P. Inflammation in atherosclerosis. Nature 2002;420:868 –74.
  2. Bayes-Genis A, Conover CA, Overgaard MT, et al. Pregnancy associated plasma protein A as a marker of acute coronary syndromes. N Engl J Med 2001;345:1022–9.
  3. Apple FS, Wu AH, Mair J, et al. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005;51:810 –24.
  4. Scirica BM, Sabatine MS, Jarolim P, et al. Assessment of multiple cardiac biomarkers in non-ST-segment elevation acute coronary syndromes: observations from the MERLIN-TIMI 36 trial. Eur Heart J 2011;32:697–705.
  5. Morrow DA, de Lemos JA. Benchmarks for the assessment of novel cardiovascular biomarkers. Circulation 2007;115:949 –52.
  6. Lindeman JH, Abdul-Hussien H, van Bockel JH, Wolterbeek R, Kleemann R. Clinical trial of doxycycline for matrix metalloproteinase-9 inhibition in patients with an abdominal aneurysm: doxycycline selectively depletes aortic wall neutrophils and cytotoxic T cells. Circulation 2009;119: 2209 –16.

Keywords: Acute Coronary Syndrome, Arrhythmias, Cardiac, Cardiovascular Diseases, Heart Conduction System, Plaque, Atherosclerotic, Pregnancy, Pregnancy-Associated Plasma Protein-A, Risk Assessment

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