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European Heart Journal Advance Access originally published online on November 2, 2007
European Heart Journal 2007 28(24):3006-3011; doi:10.1093/eurheartj/ehm488
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2007. For permissions please email: journals.permissions@oxfordjournals.org

Plasma angiogenin levels in acute coronary syndromes: implications for prognosis

Antonio Tello-Montoliu1,2, Francisco Marín1, Jeetesh Patel2, Vanessa Roldán3, Luis Mainar4, Vicente Vicente3, Francisco Sogorb1 and Gregory Y.H. Lip2,*

1 Cardiology Department, Hospital General Universitario, Alicante, Spain
2 Haemostasis, Thrombosis and Vascular Biology Unit, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UK
3 Hematology and Oncology Department, Hospital Morales Meseguer, Murcia, Spain
4 Cardiology Unit, Hospital de Requena, Valencia, Spain

Received 14 May 2007; revised 15 September 2007; accepted 28 September 2007; online publish-ahead-of-print 2 November 2007.

* Corresponding author. Tel: +44 121 507 5080; fax: +44 1722 323159/+44 121 554 4083. E-mail address: g.y.h.lip{at}bham.ac.uk


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Aims: Angiogenin is a member of the ribonuclease superfamily, which has been implicated as a mitogen of endothelial cells and activator of matrix metalloproteinases and plasminogen-activated plasmin pathways. We hypothesized abnormalities of angiogenin levels in acute coronary syndrome (ACS), with prognostic implications for predicting adverse events.

Methods and results: We measured plasma angiogenin levels (ELISA) in 396 consecutive patients (63.4% males; mean age 67 years, SD 13) admitted with ACS, who were compared with 44 ‘disease controls’ (patients with stable coronary artery disease) and 76 healthy controls. Clinical follow-up at 6 months was performed for adverse endpoints (cardiovascular death, recurrent ACS, revascularization and heart failure). ACS patients had significantly elevated plasma angiogenin levels compared with both disease controls and healthy controls (P < 0.001). After adjusting for baseline characteristics, raised troponin T levels and electrocardiographic changes, raised angiogenin levels were independently associated with more adverse events at 6 months’ follow-up [HR 1.44 (95% CI: 1.10–1.89); P = 0.008].

Conclusion: Plasma angiogenin levels are significantly increased in ACS, and may be involved in the pathogenesis of this condition. High angiogenin levels were predictive of adverse events during follow-up.

Key Words: Angiogenin • Acute coronary syndrome • Prognosis


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 
Acute coronary syndromes (ACS) have a complex and heterogeneous pathophysiology,1–3 with patients being at high risk of death and cardiac ischaemic events.4 Many pathophysiological systems have been implicated in the formation and destabilization of the culprit atheromatous plaque.3

More recently, angiogenesis has been related with the formation of new vessels through the plaque core, the rupture of which contributes to the lipid rich core release, intraplaque haemorrhage and plaque destabilization/rupture, leading to ACS.5 Several studies have suggested that vascular endothelial growth factor (VEGF), the best characterized (and probably the most important) growth factor related to neo-angiogenesis,6 and other angiogenic factors could promote atherosclerosis in animal models and potentially destabilize coronary plaques by promoting intralesional angiogenesis.7–9 Indeed, high VEGF levels have been shown to be an independent predictor of prognosis in ACS.10 Other angiogenic factors, such as angiopoietins types 1 and 2, have also been related to ACS.11

Angiogenin is a 14 124 Da soluble protein member of the ribonuclease (RNase) superfamily-enzymes of innate substrate specificity, and its pathophysiological role in angiogenesis is its most studied function.12 Indeed, angiogenin is one of the most potent angiogenic factors, with an essential role in cell proliferation.13 Various cancer types have shown greater angiogenin expression,13 compared with controls. Studies in cancer have demonstrated that high levels of angiogenin are associated with an adverse prognosis.12,14 The relation of angiogenin to VEGF in ACS and its prognosis is unreported.

We are unaware of any data on angiogenin levels in ACS, nor the relationship to prognosis in such patients. In view of the intimate relationship of angiogenesis to atherogenesis and thrombogenesis in the pathophysiology of ACS,15 we hypothesized abnormalities of angiogenin levels in ACS, with prognostic implications for predicting adverse events. We tested these hypotheses in a cross-sectional study of patients with ACS who were compared with two control groups – ‘disease controls’ (subjects with stable coronary artery disease) and ‘healthy controls’. Patients with ACS were subsequently followed up in a longitudinal study, to ascertain the influence of angiogenin levels on prognosis.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Funding
 Acknowledgements
 References
 
We prospectively recruited patients admitted to two cardiac centres with diagnosis of ACS from August 2003 to July 2005. For the purposes of this study, ACS was defined as presentation with typical ischaemic chest pain at rest (or minimal exertion) associated with electrocardiogram changes (e.g. downsloping ST segment changes ≥0.5 mm at least in two consecutive leads, T inversion of ≥0.2 mV or Q-waves more than 25% of the preceding QRS) and/or elevation of TnT levels (>0.01 ng/mL). Exclusion criteria were patients with concomitant neoplasic, infectious, connective tissue or inflammatory diseases, as these conditions have been associated with abnormal angiogenin levels.12 Of 450 patients recruited in both hospitals, 37 were not included because of the presence of at least one exclusion criterion (three with neoplastic disease, two with connective tissue disease, and 35 with infectious disease) at the moment of admission, and eight subjects did not give written consent. Additionally, nine patients did not have a blood sample for study measurements. Thus, 396 patients were finally included in this study.

All the patients received standard management as recommended for ACS, with regard to aspirin, clopidogrel, low molecular weight heparin, glycoprotein IIbIIIa inhibitors, β-blockers, statins and ACE inhibitors, as appropriate.15 In addition, the TIMI risk score was calculated in all patients.4 Patients subsequently proceeded to coronary angiography and/or revascularization (percutaneous coronary angioplasty, PTCA) and/or treadmill testing, in keeping with current management protocols, at the discretion of the admitting cardiologist.16 The extent of coronary disease was assessed by Gensini scale,17 by two different cardiologists from the Interventional Cardiology Unit of our Department.

ACS patients were compared with ‘disease controls’, who were patients with stable coronary artery disease, defined as patients with previous (>6 months) ST elevation myocardial infarct, non-ST elevation myocardial infarct or stable angina, without anginal symptoms for at least 1 month or negative treadmill test at the same time, recruited from consecutive subjects in our outpatient clinics. In addition, we recruited ‘healthy controls’, from subjects attending our Ophthalmology Unit and patient’s relatives, who were defined as ‘healthy’ by careful clinical history and physical examination, ECG, and routine blood tests. Control subjects were of similar sex and age as ACS patients. The Research Ethics Committee of our two centres approved the study, and all the subjects gave informed consent to participation.

Laboratory
Blood samples were collected in the first 48 h after admission, usually the next morning at 8:00 h with the patient fasting. Samples from control subjects (disease and healthy controls) were taken after overnight fasting and abstinence from tobacco, alcoholic or caffeine-containing beverages the evening before. All samples were collected into trisodium-citrated tubes without stasis and were centrifuged at 3500 r.p.m. for 20 min within 30 min of sample collection. Plasma samples were collected into aliquots and stored at –80°C until batch analysis.

Angiogenin and VEGF were determined by commercial ELISAs (R&D systems, Abingdon, Oxon, UK), following the manufacturer’s instructions. Intra- and inter-assay coefficients of variation were <10%, with lower limits of detection of 10 pg/mL for angiogenin and 5.0 pg/mL for VEGF. TnT levels were determined in serum samples taken at admission, 6 and 12 h, using one-step enzyme immunoassay based on electrochemoluminiscence technology (Elecsys, Roche Diagnostics, Basel, Switzerland) was used.18

Follow-up
Patients were followed up for 6 months by outpatient clinic attendance, telephone contact, and review of the medical notes. We defined ‘adverse endpoints’ as cardiovascular death (death in context of ischaemic or other heart disease, or death with unexplained cause, presumed cardiac); recurrent ACS (new episode of ACS requiring hospital admission), non-elective revascularization (emergent or urgent revascularization in context of new hospital admission) and/or admission for acute heart failure. Complete follow-up data were available in 374 patients (94.4%).

Power calculation
When we initiated this study, we were unaware of previous studies assessing the cross-sectional differences in angiogenin in ACS compared with stable CAD and controls, nor the prognostic implications, to power our study. We previously reported levels of von Willebrand factor (vWf, an index of endothelial damage/dysfunction) in stable CAD that exceeded those of healthy controls by a factor of approximately one SD.11 We therefore hypothesized a similar incremental increase of angiogenin levels (log-transformed) in subjects with ACS, i.e. that patients with ACS would have angiogenin levels increased by a further one (log-transformed) SD compared with stable CAD. To achieve this similar increase at P < 0.05 and a 1-β power of 0.9, a minimum of 23 subjects per group were required. In our previous study of 156 subjects with ACS,11 48 patients (31%) had experienced at least one adverse event during 30 days, and 48 h vWf levels were >50% in these subjects. Given improvements in ACS management and outcomes, we more conservatively predicted that only 20% of our cohort would experience at least one adverse event at 6 months’ follow-up. Thus, we decided to recruit over twice as many patients (n = 396) to ensure adequacy of power and to allow for any potential losses to follow-up.

Statistical analysis
Continuous variables were tested for normal distribution by Kolmogorov–Smirnov test. Continuous variables are presented as mean ± SD or median (IQR, interquartile range), as appropriate, and categorical variables as percentage. Comparisons between groups were performed by one-way ANOVA (or Kruskall–Wallis test), as appropriate, with Tukey’s post hoc test for inter-group comparisons. Categorical data were compared using the {chi}2-test, and a Fisher’s exact test was performed, if relevant. Correlations between two continuous variables were performed using the Pearson correlation coefficient, or Spearman rank correlation, if the variables were not normally distributed. To explore the prognostic influence of angiogenin levels, we defined an ordinal scale for median angiogenin levels (where score = 1 is angiogenin <199 ng/mL, 2 is 200–299 ng/mL, 3 is 300–399 ng/mL, and 4 is ≥400 ng/mL), given the need for clinicians to explore a ‘cut-off’ value for a biomarker to predict adverse effects. Secondly, we also explored influence of angiogenin as a continuous variable.

The overall recurrence-free survival rates were calculated using the Kaplan–Meier method, and the differences determined using the log-rank test. The independent effect of variables on prognosis was calculated using a Cox proportional hazards multivariable regression model (Enter Method), including those clinical, ECG, and biological markers (troponin and angiogenin), incorporating in the model only those values with P < 0.15 in a univariable analysis, calculating also hazard ratio (HR) and 95% of confidence interval. All P-values <0.05 were accepted as a statistically significant. Statistical analysis was performed using SPSS 11.0 for Windows (SPSS, Inc., Chicago, IL, USA).


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 Acknowledgements
 References
 
We studied 396 consecutive patients admitted with ACS (mean age 67.4 ± 15.1 years; 63.4% males) (Table 1), of whom 197 patients (49.7%) had troponin-T levels of >0.1 mg/mL, and 236 (59.6%) underwent coronary angiography. Severe anginal symptoms (defined as ≥2 anginal events in 24 h prior to admission) were recorded in 96 (24.4%) patients. More than a half of these patients (59.8%) underwent cardiac catherization, and on the Gensini scale, the severity of their coronary artery disease at angiography was 12.41 ± 4.02.


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  		Table 1 Baseline characteristics of patients and controls

 
Angiogenin levels were highest in ACS patients (P < 0.0001), compared with controls (Table 1, Figure 1). There were no significant differences in angiogenin levels between ‘disease controls’ and ‘healthy controls’ (P = 0.917). Patients who presented with TnT ≥ 0.1 mg/mL had significantly higher median angiogenin levels [254.3 (214.0–338.5) vs. 235.7 (185.6–330.4) ng/mL; P = 0.015]. There was no significant correlation between angiogenin levels and TIMI risk score (Spearman, r = 0.032; P = 0.591). There was no significant correlation of Gensini scale and angiogenin levels (r = 0.17; P = 0.230). There were also no significant differences in angiogenin levels in relation to baseline medical therapy taken by the patients (Table 2).


Figure 1
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  		Figure 1 Angiogenin levels in acute coronary syndrome, stable coronary artery disease (disease controls) and healthy controls [values are median (IQR), and ACS = acute coronary syndrome].

 

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  		Table 2 Angiogenin levels in relation to different modalities of drug therapy

 
There were no significant differences in VEGF levels between the study groups (P = NS). Only two patients of our study would fit the criteria of ‘high risk’ ACS patients, and their VEGF values were 80.33 and 46.86 pg/mL. There was no significant correlation between VEGF levels and angiogenin levels (r = 0.054, P = 0.312).

Longitudinal analysis
Complete follow-up data were available in 374 patients (94.4%), of whom 93 patients (24.8%) sustained adverse events over the 6-month follow-up period: cardiovascular death in 26 (6.9%), recurrent non-ST segment elevation ACS in 47 (12.6%), new ST elevation ACS in 3 (0.8%), non-elective coronary artery by-pass grafting in 4 (1%), and acute heart failure in 13 (3.5%).

In univariable Cox regression analysis, high plasma angiogenin levels (≥400 ng/mL) were a significant predictor of adverse outcomes [HR 1.38 (1.11–1.71); P = 0.003]. Kaplan–Meier curves show that those with the highest levels of angiogenin (≥400 ng/mL) had a significantly worse prognosis than the three subgroups at lower levels (angiogenin <199 ng/mL levels; 200–299 ng/mL or 300–399 ng/mL) (log-rank test, P < 0.01; Figure 2).


Figure 2
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  		Figure 2 Kaplan–Meier curve showing the effects of high angiogenin levels on adverse events following admission with acute coronary syndrome [patients with raised angiogenin levels (Ang ≥ 400 ng/mL) had a significantly worse outcome compared with patients with lower angiogenin levels (<199 ng/mL; 200–299 ng/mL; and 300–399 ng/mL) at 6 months’ follow-up (log-rank test, P = 0.01)].

 
In a multivariable Cox regression analysis (Table 3), age ≥ 65 years [HR 2.31 (1.26–4.26); P = 0.007], the presence of several anginal symptoms [HR 2.22 (1.34–3.68); P = 0.002] and high angiogenin levels [HR 1.44 (1.10–1.89); P = 0.008] were independent predictors of adverse outcomes. When the multivariable analysis was repeated using angiogenin levels as a continuous variable, angiogenin was still a significant predictor of adverse outcomes [HR 1.002 (1.001–1.004); P = 0.007] (Table 3). This predictive value of adverse outcomes also remained, even when we only analysed patients without TnT elevation, using the standard cut-off point (P = 0.0147). TIMI risk score was also a significant predictor of adverse outcomes [HR 1.45 (1.25–1.68); P < 0.0001) at 6 months’ follow-up.


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  		Table 3 Cox regression analysis at 6 months’ follow-up

 
In the Cox regression analysis, the highest quartile of plasma VEGF levels (≥45.8 pg/mL) was not predictive of adverse events at 6 months’ follow-up.


   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 Acknowledgements
 References
 
This is the first study demonstrating abnormalities of plasma angiogenin in ACS, and the role of this factor in prognosis. Indeed, patients with ACS had significantly higher angiogenin levels than patients with stable coronary artery disease (disease controls), potentially reflecting the role of this molecule in the early phase of ACS. Importantly, high angiogenin levels were prognostically important at 6 months' follow-up, with regard to adverse cardiovascular events.

Angiogenin is a potent angiogenic growth factor related to endothelial cell proliferation.12,13 In animal models such as the chick chorioallantoic membrane and rabbit cornea assays, angiogenin is one of the most potent angiogenic factors.19 Indeed, angiogenin may be required for other angiogenic factors (e.g. beta fibroblast growth factor and VEGF) to stimulate angiogenesis. With reduced angiogenin levels, cells display a reduced capacity to induce tumour growth and angiogenesis, despite elevated beta fibroblast growth factor and VEGF levels.14 In the clinical setting, angiogenin has been studied in different pathological situations, especially in cancer.14,20,21 Despite the increasing recognition that angiogenesis features in the pathophysiology of atherothrombosis, we are only aware of one study of angiogenin in arterial disease, where Burgmann et al.22 analysed 67 patients with peripheral occlusive arterial disease, and reported higher angiogenin levels in patients with more severe peripheral occlusive arterial disease (stage IV) in comparison with disease (deep vein thrombosis) and healthy controls.

Angiogenesis has been related to the atherosclerotic process, mainly in the development of micro-vessels inside the core of the atherosclerotic plaque.5 These vessels are thin-walled and are lined by a discontinuous endothelium, without supporting smooth-muscle cells.23 This characteristic confers vulnerability to the vessel wall and the possibility of rupture. Moreover, intraplaque haemorrhage and rupture of the fibrous cap are associated with an increased density of micro-vessels.24,25 Typically, intraplaque haemorrhage destabilizes the atherosclerotic plaque, leading to occlusive thrombosis and clinical presentation with ACS.2 Angiogenin plays an important role in interactions involving wound healing activating proteases, such as the metalloproteinase family,26,27 and stimulating tissues plasminogen activator to produce plasmin.27 These proteases have also been related to the destabilization of atherosclerotic plaque.28,29 Taken together, these findings suggest that high levels of angiogenic factors could be surrogate markers of unstable plaque in ACS.

Angiogenesis is a complex biological process, which requires the precise coordination of multiple steps, involving a large variety of effector molecules.30 Some of these effector molecules (e.g. VEGF) have been well studied in coronary artery disease, including ACS.10 Other pro-angiogenic molecules that have been studied in ACS include hepatocyte growth factor,10 angiopoietins types 1 and 2, and angiopoietin receptor Tie-2,11 and pregnancy-associated plasma protein-A.31 In all studies, patients presenting with ACS had significantly higher levels of pro-angiogenic effector molecules compared with (usually healthy) controls. The present study is in broad agreement with these observations, and adds to the data on a pro-angiogenic stimulus in ACS, with such patients having significantly higher levels of angiogenin, compared with those with stable coronary artery disease controls.

In contrast to previous studies, VEGF levels were generally low in our population, with levels below the lower limit of detection in approximately half the study population. This may perhaps be related to the (lower) initial risk status of our patients in comparison with previous studies11 and improved cardiovascular prevention strategies (blood pressure control, statins, ACE inhibitors, etc.). As mentioned above, angiogenin is required for VEGF to stimulate angiogenesis.14 Thus, only sufficiently ‘high risk’ ACS patients with elevations of angiogenin levels would ‘drive’ an increase in plasma VEGF levels. This hypothesis would need to be explored in a cohort of ‘high(er) risk’ ACS subjects. Nonetheless, high angiogenin levels were independently related to adverse prognosis following ACS. Similarly, hepatocyte growth factor and VEGF have been shown to have independent prognostic implications at 6 months’ follow-up,10 in agreement with our results. Thus, angiogenin (or other progiogenic factors) could not only be a marker of unstable plaque during the acute event, but could be a risk marker of future events. Although, similar angiogenin plasma levels in disease controls and healthy controls could be a limitation for use as a risk stratification tool.

One of the most routinely used clinical risk scores in the setting of ACS is the TIMI risk scale,4 which contains variables such as age ≥ 65 years old, ≥3 risk factors, severe anginal symptoms, aspirin use in last 7 days, ST segment changes (downsloping) and raised TnT levels. Whilst this scale was independently related to prognosis in our population, there was no significant statistical correlation to angiogenin levels.

This study is limited by the measurement of single baseline sample in determining prognosis. Of note, our ‘disease controls’ had broadly similar plasma levels of angiogenin than healthy subjects. This observation may mean the normalization of angiogenin plasma levels with time, following an ACS. Another limitation could be the effect of drugs, which are used in the management of ACS, especially since some drugs (e.g. statins) may affect different pathophysiological systems in coronary artery disease, including angiogenesis.32 We also had a relatively short follow-up period (6 months) and further studies on temporal changes in angiogenin with long-term follow-up are needed. Given the need for further studies, we cannot recommend screening ACS patients for angiogenin or the monitoring of angiogenin levels in patients with ACS at this stage, but this study re-emphasizes that angiogenesis is important in ACS and the role of angiogenin should be further explored in the pathophysiology of this ischaemic heart disease, raising possibilities of new therapeutic targets.

In conclusion, plasma angiogenin levels are significantly increased in ACS, and may be involved in the pathogenesis of this condition. High angiogenin levels were predictive of adverse events.


   Funding
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
Acknowledgements
 References
 
We acknowledge the support of the Sandwell and West Birmingham Hospitals NHS Trust for the Haemostasis Thrombosis, and Vascular Biology Unit. This study was supported by a grant from Spanish Society of Cardiology.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
References
 
We thank Drs Irene Chung and Anirban Choudhury for help with data collection. We thank Dr José Sánchez-Payá for help with statistical analysis.

Conflict of interest: none declared.


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 Acknowledgements
 References
 

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R. P. Giugliano and E. Braunwald
The Year in Non-ST-Segment Elevation Acute Coronary Syndrome
J. Am. Coll. Cardiol., September 23, 2008; 52(13): 1095 - 1103.
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