• 
• 

Three Part Question

In [patients with suspected acute myocardial ischaemia] do [normal placental growth factor levels in peripheral plasma] enable [accurate exclusion of acute coronary syndromes]?

Clinical Scenario

A fifty year-old man presents with tight central chest pain for thirty minutes. There are no abnormalities on physical examination and his initial ECG is normal. He asks, "Is it my heart, doctor?".
You explain that you cannot be certain but will do a blood test to make sure he hasn't had a heart attack in twelve hours time. He looks confused. You wonder why the triage of cardiac chest pain is still so difficult in the 21st century. Surely there is a better way of excluding acute coronary syndromes. Having heard about placental growth factor as a promising cardiac biomarker, you wonder if there is any evidence that it would be useful in this situation.

Search Strategy

OVID Medline 1966 - 2005 September Week 2
Embase via Dialog Datastar 1974 - September 2005
Medline:
(exp Myocardial Infarction/ OR exp Angina, Unstable/ OR exp Coronary Thrombosis/ OR exp Chest Pain/ OR (myocard$ adj (infarct$ OR ischem$ OR ischaem$)).mp. OR (ACS OR MI OR AMI OR acute coronary syndrome OR unstable angina OR heart attack$.mp.) AND (placental growth factor OR PlGF).mp. limit to human and English language
Embase:
(ACUTE-HEART-INFARCTION#.DE. OR HEART-INFARCTION#.DE. OR HEART-MUSCLE-ISCHEMIA#.DE. OR CORONARY-ARTERY-OBSTRUCTION#.DE. OR CORONARY-ARTERY-THROMBOSIS#.DE. OR UNSTABLE-ANGINA-PECTORIS#.DE. OR (acute ADJ coronary ADJ syndrome OR ACS OR AMI OR MI OR unstable ADJ angina OR heart ADJ attack).MP. OR (myocard$ ADJ (infarct$ OR ischem$ OR ischaem$)).MP.) AND (PLACENTAL-GROWTH-FACTOR#.DE. OR (placental ADJ growth ADJ factor OR PlGF).MP.) limit to human and English language

Search Outcome

Altogether five papers were identified in Medline and 220 in Embase. One was relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Heeschen et al 2004 Germany	1). 547 patients enrolled in the CAPTURE trial, who had recurrent resting chest pain with ECG changes during treatment with IV heparin and GTN, had >70% stenosis on coronary angiography and had been randomised to receive placebo (not abciximab). Blood taken a mean of 8.7 hours after symptom onset. 2). 626 consecutive patients presenting to the Emergency Department with acute chest pain and no ST segment elevation. Blood taken at presentation (mean 5.1 hours from symptom onset).	Prospective observational cohort study	PlGF for prediction of adverse events in the CAPTURE subgroup	PlGF an independent predictor of 30-day (HR 3.03, P<0.001) and 6-month (HR 3.37, P<0.001) cardiac risk. Area under ROC curve 0.72. PlGF a stronger predictor than CRP.	Gold standards for diagnosis of cardiac v. non-cardiac pain did not include troponin estimation. Sensitivity, specificity, PPV and NPV of PlGF for diagnosis of ACS or prediction of adverse events not reported.
			PlGF levels according to diagnosis in Emergency Department population	Significantly increased in NSTEMI and UA compared with SA and non-cardiac pain (P<0.001 for each). No significant difference between NSTEMI and UA.
			Correlation of PlGF levels with other markers in Emergency Department population	No correlation with TnT (r=0.07) or sCD40L (r=0.12); positive correlation with CRP (r=0.43, P<0.001).
			PlGF for prediction of 30-day adverse events in Emergency Department population	At a cut-off of 27ng/L, 21.2% of patients with high PlGF levels and 5.3% with low levels had an adverse event (P<0.001). PlGF an independent predictor on multivariable analysis (HR 3.01, P<0.001).
			Performance of PlGF + TnT + sCD40L for prediction of adverse events in Emergency Department population	2.1% adverse event rate if negative for all three markers.

Comment(s)

Placental growth factor (PlGF) belongs to the same family as vascular endothelial growth factor (VEGF) and stimulates angiogenesis by activating VEGF receptors (de Falco et al, 2002). VEGF and its homologue PlGF have both pro- and anti-arteriosclerotic actions. By stimulating angiogenesis in ischaemic heart, VEGF improves collateral blood flow and has been investigated as a therapeutic intervention in ischaemic heart disease, albeit with mixed results (Post et al, 2000). Recently, there has been growing evidence for the pro-arteriosclerotic effects of VEGF. It induces intraplaque angiogenesis, enabling plaque expansion (Celletti et al, 2001). Further, VEGF stimulates expression of cell adhesion molecules and chemotactic molecules, which enhance migration of leucocytes into atheroma, leading to plaque expansion and destabilisation (Kim, et al, 2000; Marumo et al, 1999). PlGF has been shown to have similar proatherogenic properties (Khurana et al, 2005). In addition, by displacing VEGF from the VEGF-1 receptor, it increases the fraction of VEGF available to activate the VEGF-2 receptor, thus stimulating angiogenesis (Carmeliet et al, 2001). Whereas VEGF plays an essential role in both physiological and pathological angiogenesis, the role of PlGF is restricted to pathological conditions (Auterior et al, 2003; Iyer et al, 2002). As it is upregulated in ischaemic myocardium and plays a key role in the expansion of atheroma, PlGF is an attractive candidate for a novel cardiac biomarker (Lutten et al, 2002). There is little evidence for the clinical use of PlGF as a cardiac biomarker in the Emergency Department. The only study to have investigated its use found it to be a powerful independent predictor of adverse cardiac events in both high-risk ACS and in the undifferentiated Emergency Department population. Levels were significantly higher in ACS patients than in non-ACS patients. Further, as PlGF did not correlate with troponin levels, the two markers may provide complementary prognostic information. However, over 5% of patients with a negative PlGF experienced a cardiac event within 30 days and TnT was a more powerful independent predictor of this outcome. It is important for future research to evaluate the utility of PlGF as a cardiac biomarker. Combination with other markers may improve diagnostic accuracy and prognostic stratification.

Editor Comment

Abbreviations: ACS: acute coronary syndrome; GTN: glyceryl trinitrate; NSTEMI: non-ST elevation myocardial infarction; UA: unstable angina; PPV: positive predictive value; NPV: negative predictive value; HR: hazard ratio; PlGF: placental growth factor; TnT: troponin T

Clinical Bottom Line

There is little evidence for the use of placental growth factor as a cardiac biomarker, but early evidence is promising. Further research is necessary.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

1. Heeschen C; Dimmeler S; Fichtlschere S; Hamm CW; Berger J; Simoons ML; Zeiher AM; CAPTURE Investigators. Prognostic value of placental growth factor in patients with acute chest pain Journal of the American Medical Association 2004; 291(4): 435-441
2. De Falco S; Gigante B; Persico G. Structure and function of placental growth factor Trends in Cardiovascular Medicine 2002; 12: 241-246
3. Iyer S; Acharya KR. Role of placental growth factor in cardiovascular health Trends in Cardiovascular Health 2002; 12: 128-134
4. Luttun A; Tjwa M; Moons L; Wu Y; Angelillo-Scherrer A; Liao F; Nagy JA; Hooper A; Priller J; De Klerck B; Compernolle V; Daci E; Bohlen P; Dewerchin M; Herbert JM; Fava R; Matthys P; Carmeliet G et al Revascularization of ischemic tissues by PlGF treatment, and inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1 Nature Medicine 2002; 8(8): 831-840
5. Khurana R; Moons L; Shafi S; Luttun A; Collen D; Martin JF; Carmeliet P; Zachary IC. Placental growth factor promotes atherosclerotic intimal thickening and macrophage accumulation Circulation 2005; 111(21): 2828-2836
6. Autiero M; Luttun A; Tjwa M; Carmeliet P. Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and ... Journal of Thrombosis and Haeomstasis 2003; 1: 1356-1370