Type II secretory phospholipase A2: The emerging role of biochemical markers of plaque inflammation

Jan J. Pieka,* and Robbert J. de Wintera

a Amsterdam Medical Center, Cardiologie, Meibergdreef 9, postbus 22660, 1100 DD Amsterdam, Netherlands

* Corresponding author: Prof. J. J. Piek. Tel.: +31-20-5662609; fax: +31-20-6962609

Received 22 August 2003; accepted 28 August 2003

See doi:10.1016/j.ehj.2003.07.003for the article to which this editorial refers

In his classical clinical-pathomorphological studies, Fulton described for the first time the thrombotic sequelae underlying acute coronary events.1However, it took several decades before these thrombo-embolic complications were related to local plaque composition and the extent and/or location of plaque inflammation. Subsequent studies were conducted using atherosclerotic plaque specimen derived by directional coronary atherectomy during cardiac catheterization. These studies demonstrated that the clinical manifestation of coronary syndromes is positively associated with the extent of plaque inflammation of the culprit lesions, i.e. patients with unstable angina exhibit more activated macrophages and/or T-lymphocytes and less smooth muscle cells as compared to patients with stable angina.2The intimal infiltration of activated macrophages and/or T-lymphocytes promotes plaque rupture and subsequent local thrombus formation resulting in micro-embolization and/or acute thrombotic occlusion resulting in acute coronary syndromes.

In view of its clinical relevance, numerous studies have been performed to determine plasma markers representing the extent of plaque inflammation. In particular, C-reactive protein (CRP) has been extensively investigated.3Plasma levels of CRP were positively associated with the number of cardiovascular risk factors. High plasma levels of CRP (>3mg/l) are predictive of future cardiovascular events in individuals without a history of cardiovascular disease, in patients with peripheral disease and patients with stable and unstable angina. Furthermore, baseline CRP is a predictor of cardiac events following percutaneous coronary interventions (PCI). Currently, large scale prospective clinical trials are conducted in healthy subjects and patients with an abnormal CRP to establish the potential benefit of the reduction of systemic inflammation, e.g. with lipid lowering therapy.

More recently, type II secretory phospholipase A2 (sPLA2) has been recognized as an independent predictor of cardiovascular events. It is postulated that the tissue expression of sPLA2is one of the links between inflammatory processes and lipid accumulation in atherosclerosis. This enzyme is present in the media of normal and diseased arteries and hydrolyzes phospholipids at the sn-2 position generating lysophospholipds and fatty acids. The local production of oxidized low density lipoprotein results in enhanced uptake by macrophages and subsequent transformation into foam cells. sPLA2exhibits similar features like CRP as marker of plaque inflammation. This includes its positive association with cardiovascular risk factors, the link between enhanced plasma levels (245ng/dl) and the occurrence of coronary events both in patients with stable and unstable angina.4

The study of Ping-Yen Liu et al. in this issue of the journal adds to our current knowledge on the role of plasma markers of plaque inflammation relevant for patient management. They performed in a meticulous fashion a direct comparison between the alterations of plasma levels of sPLA2, CRP, creatine kinase (CK), CK-MB and troponin-T prior to PCI, directly after and at 24 and 48h after PCI, respectively, in 247 patients with predominantly stable angina. A total of 137 patients were treated with balloon angioplasty only, while 110 patients were treated with stent-implantation. A total of 100 patients with normal coronary arteries served as a control group. PCI induced a rapid increase in sPLA2(within 24h) as compared to the other parameters and a high level (>50ng/dl) measured at 24h was, next to smoking and diabetes mellitus, an independent predictor of cardiac events during a 2 years follow-up period (completed in 236 of the 247 patients). A high level of sPLA2after PCI was a frequent finding (146 of the 236 patients), associated with higher prevalence other risk factors such as hypertension, diabetes mellitus and smoking. The incidence of coronary events in this group was higher compared to patients (n=90) with a low level of sPLA2(46% vs 22%, P<0.001). Remarkably, CRP prior to PCI did not appear to be a predictor of subsequent events in this study of relative small sample size. Balloon angioplasty or stent-implantation showed similar alterations in plasma levels of the aforementioned markers. The analyses did not include a risk model involving, next to sPLA2, the other independent predictors (smoking, diabetes mellitus) to assess a patient’s individual risk. Moreover, there was no information on smoking behaviour or diabetes control during follow up and/or the use of lipid lowering therapy (at the time of PCI in 34% of the patients).

1. Revascularization procedures

Repeat revascularizations were performed in 17% (15 repeat angioplasty, 10 bypass surgery) of the patients with high levels of sPLA2after PCI compared to 13% (8 repeat angioplasty, 4 bypass surgery) of the patients with low levels of sPLA2. This finding is in accordance with a recent report in a large cohort of patients on the prognostic value of CRP prior to PCI on the clinical outcome after elective angioplasty.5The incidence of repeat revascularization was similar in those patients with an elevated and normal CRP levels. This indicates that the process of vascular remodelling and/or smooth muscle cell proliferation after PCI is not determined by the extent of plaque inflammation as determined by the level of plasma markers. Similar observations were reported in clinical studies using atherectomy specimen from culprit lesions in patients with stable and unstable angina. The incidence of clinical restenosis was not associated with the extent of plaque inflammationassessed by immunohistochemistry of activated macrophages and T-lymphocytes. However, there was a positive association with the clinical presentation of restenosis, i.e. patients with a low grade of initial plaque inflammation presented recurrent symptoms more often as stable angina in contrast to patients with a high grade of plaque inflammation presenting recurrent symptoms more often as unstable angina.6These findings suggests that the extent of initial plaque inflammation is not a predominant factor influencing vascular remodeling and/or smooth muscle cell proliferation induced by PCI but is rather responsible for the clinical manifestation of recurrent symptoms. This supports the hypothesis that the smoldering effects of the inflammation may destabilize repair tissue responsible for the severity of anginal symptoms during follow-up after PCI.

2. Death, unstable angina and myocardial infarction

The incidence of the combined cardiac endpoint death, unstable angina and myocardial infarction was 29% (7 cardiac deaths, 14 unstable angina, 21 myocardial infarctions) in the patients with high levels of sPLA2after PCI compared to 9% (3 cardiac deaths, 5 unstable angina) with low levels of sPLA2after PCI (P<0.001). Numerous studies on the prognostic value of CRP in obstructive artery disease underline the importance of this parameter for risk stratification. The results of the present study, that involves a direct comparison between the different biochemical markers, indicate that sPLA2may be, next to CRP, a more useful marker to predict cardiac events than after PCI. These preliminary findings warrant confirmation in a larger cohort of patients. This is in particular relevant as almost half of patients undergoing elective PCI exhibit high levels of sPLA2after PCI and pertain an enhanced risk to develop cardiac events. It is at present unknown if this potential risk for cardiac events can be reduced by cessation of smoking or optimal treatment of diabetes mellitus. Furthermore, the potential beneficial role of lipid lowering therapy as a resultof its anti-inflammatory effect remains unclear and requires further evaluation. Its significance is underscored in recent studies showing that statin therapy before PCI is associated with a reduction in mortality in patients with abnormal CRP levels, while withdrawal of statin therapy after PCI enhances the risk of cardiac events.7,8One could anticipate a reduction of cardiac events after aggressive lipid lowering therapy in a larger proportion of the patients. In this respect, the West of Scotland Coronary Prevention Study pertains interesting information.9In this primary prevention study in men with hypercholesterolemia, sPLA2appeared to be a strong risk factor for a coronary event, independent of other markers of inflammation or classic risk factors. This increase of risk with increased sPLA2levels was as strong in men who received pravastatin as in those who received placebo. This indicates that sPLA2may be a novel target to guide anti-inflammatory therapy in addition to the valuable effect of lipid lowering therapy.

The present study on the prognostic value of sPLA2in patients undergoing elective PCI is an interesting hypothesis generating study that warrants confirmation in a larger cohort of patients. Furthermore, it requires a more extensive evaluation of the effect of risk factor reduction in patients with enhanced plasma levels of sPLA2. Finally, it may open new pathways for novel pharmacological agents using sPLA2as a target to influence this link between inflammation and atherogenesis. The message of this study is clear: ‘Dilate the lesion, but use this opportunity to treat the disease.’

References

  1. Fulton WFM. The coronary arteries: arteriography, microanatomy and pathogenesis of obliterative coronary artery disease. Chas Thomas, Springfield 1965..
  2. van der Wal AC, Becker AE, Koch KT et al. Clinically stable angina pectoris is not necessarily associated with histologically stable atherosclerotic plaques. Heart. 1996;76:312–316.[Abstract]
  3. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation. 2003;107:363–369.[Free Full Text]
  4. Kugiyama K, Ota Y, Sugiyama S et al. Prognostic value of plasma levels of secretory type II phospholipase A2 in patients with unstable angina pectoris. Am J Cardiol. 2000;86:718–722.[CrossRef][Medline]
  5. de Winter RJ, Koch KT, van Straalen JP et al. C-reactive protein and coronary events following percutaneous coronary angioplasty. Am J Med. 2003;115:85–90.[CrossRef][Medline]
  6. Meuwissen M, Piek JJ, van der Wal AC et al. Recurrent unstable angina after directional coronary atherectomy is related to the extent of initial coronary plaque inflammation. J Am Coll Cardiol. 2001;37:1271–1276.[CrossRef][Medline]
  7. Chan AW, Bhatt DL, Chew DP et al. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation. 2003;107:1750–1756.[Abstract/Free Full Text]
  8. Heeschen C, Hamm CW, Laufs U et al. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105:1446–1452.[Abstract/Free Full Text]
  9. Packard CJ, O’Reilly DSJ, Caslake MJ et al. Lipoprotein-associated phospholipase A2 as an independent predictor of coronary heart disease. N Engl J Med. 2000;343:1148–1155.[Abstract/Free Full Text]

Related articles in EHJ:

Prognostic value and the changes of plasma levels of secretory type II phospholipase A2 in patients with coronary artery disease undergoing percutaneous coronary intervention
Ping-Yen Liu, Yi-Heng Li, Wei-Chuan Tsai, Ting-Hsing Chao, Liang-Miin Tsai, Hua-Lin Wu, and Jyh-Hong Chen
EHJ 2003 24: 1824-1832. [Abstract] [Full Text]  




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