The mean pregnancy-associated plasma protein A (PAPP-A) levels of patients who presented with chest pain at a hospital were higher in patients who went on to have a cardiovascular event within 90 days than in patients who did not have an event. These findings, which suggest that PAPP-A has prognosticative value in predicting major cardiac events, were published online March 18 in the Canadian Medical Association Journal.
Markers of unstable plaques would be useful in identifying patients without myocardial necrosis who are at risk of major cardiac events. Several small studies have identified PAPP-A, a peptide that is secreted during pregnancy but also in unstable atherosclerotic plaques, as a potential tool to stratify risk in patients with coronary artery disease. Stephan von Haehling, MD, PhD, of Charité Medical School, Campus Virchow-Klinkum in Berlin, and colleagues conducted this large prospective study in an attempt to confirm the findings of the smaller studies.
The researchers evaluated 4,038 consecutive patients who presented with chest pain at University Hospital Tübingen in Germany, between December 2007 and April 2009. The researchers excluded from the study patients whose chest pain was not caused by cardiac issues, those who received heparin, and those with incomplete data. Each of the 2,568 patients included in the study underwent coronary angiography within 24 hours and received an echocardiogram within 48 hours.
Acute coronary syndrome (ACS) was diagnosed in 1,229 of the patients and stable angina was the diagnosis for 1,339. All patients were followed for 90 days or until death, and no patients were lost to follow-up. The primary outcome was a composite of stent thrombosis, MI, ischemic stroke or cardiovascular-related death.
The normal level of PAPP-A in men and non-pregnant women is less than 14 mlU/L. PAPP-A levels in the study cohort ranged from 4.1 mlU/L to 2,154.4 mlU/L (excluding the patient at the high end of the range, the remaining patients all had PAPP-A levels of 276.2 mlU/L or lower). There was no significant difference according to gender, but patients with ACS had higher levels than patients with stable angina (24.8 mlU/L vs. 24.4 mlU/L).
There were 203 patients who experienced 245 primary outcome events. These patients had a mean PAPP-A level of 62 mlU/L compared with a mean level of 21.4 mlU/L in those who did not experience a primary outcome event. The researchers performed a Cox proportional hazard analysis on several variables to determine their predictive value for the short-term occurrence of primary outcome events, and determined that PAPP-A level was the strongest predictor for the entire cohort and also when the analysis was restricted to just the ACS patients or the stable angina patients. A Kaplan-Meier survival curve found that PAPP-A levels above 34.6 mlU/L were a strong predictor of short-term cardiac events (hazard ratio 5.3).
The researchers noted that their study could not determine whether PAPP-A is pro-inflammatory or a suppressor of inflammation. But the study did confirm the findings of smaller studies that indicated that PAPP-A was a good independent marker of unstable atherosclerotic plaques.
As limitations, the researchers noted that only baseline serum samples were available, and therefore they could not determine whether follow-up samples may have better predictive value. They also acknowledged that not all patients with chest pain undergo cardiac catheterization and that further studies on the predictive value of PAPP-A levels on patients who do not undergo catheterization are necessary. Finally, although the study was large it was conducted at a single center, and the researchers suggested that a multicenter trial should be undertaken to confirm their results.