Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 13, Number 16, 2007

Contents

Modifying Coronary Risk Factors: C-Reactive Protein, Haemostatic Factors and Cardiovascular Risk
Executive Editor: Aurelio Leone


Editorial: Pp. 1617-1618


C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders? Pp. 1619-1629
C.L. Smith
[Abstract]


C-Reactive Protein: Interaction with the Vascular Endothelium and Possible Role in Human Atherosclerosis Pp. 1631-1645
C. Ferri, G. Croce, V. Cofini, G. De Berardinis, D. Grassi, R. Casale, G. Properzi and G. Desideri
[Abstract]


Fibrinogen: A Predictor of Vascular Disease Pp. 1647-1659
A.I. Kakafika, E.N. Liberopoulos and D.P. Mikhailidis
[Abstract]


Smoking, Haemostatic Factors, and Cardiovascular Risk Pp. 1661-1667
A. Leone
[Abstract]


Platelets and Vascular Risk: An Option for Treatment Pp. 1669-1683
I.A. Jagroop, A.I. Kakafika and D.P. Mikhailidis
[Abstract]


Platelets in Atherothrombosis: New and Evolving Roles Pp. 1685-1691
A. Weyrich, F. Cipollone, A. Mezzetti and G. Zimmerman
[Abstract]


C-Reactive Protein and Hypertension: Is there A Causal Relationship? Pp. 1693-1698
A. Virdis, L. Ghiadoni, Y. Plantinga, S. Taddei and A. Salvetti
[Abstract]


Circulating Endothelial Progenitor Cells Characterization, Function and Relationship with Cardiovascular Risk Factors Pp. 1699-1713
A. Balbarini, M.C. Barsotti, R. Di Stefano, A. Leone and T. Santoni
[Abstract]


COX-2: Friend or Foe? Pp. 1715-1721
A. Iezzi, C. Ferri, A. Mezzetti and F. Cipollone
[Abstract]




Abstracts


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Editorial: Modifying Coronary Risk Factors: C-Reactive Protein, Haemostatic Factors and Cardiovascular Risk

There has been conflicting debate about the relationship among those parameters which are generally involved in cardiovascular events such as C-Reactive Protein, haemostatic factors and other major cardiovascular risk factors. The debate seems to be a result for establishing the exact mechanisms of cardiovascular damage, that is believed to be due to either a direct action on coagulation/fibrinolysis cascade components either a consequence of interaction between haemostatic factors, inflammatory factors and the other cardiovascular risk factors.

Cardiovascular damage expresses itself mainly as thromboembolic damage because of structural and biochemical components of coagulation/fibrinolysis cascade involved.

Clot formation and lysis involve a large series of structures at different levels: vascular level, cellular level, and plasmatic level. Physiologically, the whole mechanism is directed to stop haemorrhage and keep vessel lumen patency. Damage at any of these levels may cause alterations potentially harmful against cardiovascular system.

After a vasoconstriction following a stimulus of different types, endothelium is the first structure involved in coagulation/ fibrinolysis cascade.

If the endothelium is intact, physiological stimulation not only causes vessel vasodilation, but also protects the vessel wall against the development of atherosclerosis and thrombotic vascular events. On the contrary, in presence of endothelial damage and/or dysfunction a series of occurrences produced by biochemical factors activates platelets (cellular level) that increase their secretion, adhesiveness, and aggregation initiating those processes that, in case of pathological response, may lead to thrombi formation. Plasmatic factors (plasmatic level) mainly fibrinogen and fibrin, together a reduced activity of plasminogen activators, impair further the phenomenon.

The interference with other cardiovascular risk factors increases heavily the appearance of cardiovascular events by a complex series of chemical, biological, and inflammatory mechanisms, the exact action of which has yet to be clarified. However, C-Reactive Protein and haemostatic system alterations play a fundamental part in causing cardiovascular events.

The paper of Carolyn Smith from London [1] underlines the role of ADMA as a mediator of cardiovascular disorders as well as its relationship with C-reactive protein.

The complex interaction between C-reactive protein with the vascular endothelium is widely discussed by Claudio Ferri and Coworkers [2] from the University of L’Aquila, Italy. Human atherosclerosis is characterized by a multifactorial etiology, but endothelial dysfunction has a significant role in determining the appearance of atherosclerotic alterations.

Among haemostatic factors, three papers [3-5] discuss the role of fibrinogen as a predictor of vascular disease, the interference of smoking with coagulation-fibrinolysis cascade, and the mechanisms by which platelets may be related to cardiovascular risk as well as those measures able to prevent cardiovascular damage. Moreover, the new role played by platelets in atherothrombosis is widely discussed by Weyrich and Coworkers [6].

The relationship between C-reactive protein and hypertension [7] is discussed by Virdis and Coworkers of Pisa, Italy. Nowdays, there is no clear evidence of a strong link between those two factors.

An emerging role to explain many hypotheses of cardiovascular risk seems to be due to the knowledge of the circulating endothelial progenitor cells. The paper of Balbarini and Co-workers [8] clarifies the physiologic characteristics of the circulating endothelial progenitor cells as well as their relationship with cardiovascular risk.

Finally, an overview of the relevant biology and pharmacology of COX 2 in atherosclerosis [9] is assessed in the paper of Iezzi and Coworkers from Chieti and L’Aquila, Italy.

The articles in this issue provide a current summary to how understand the mechanisms and interactions of the main cardiovascular risk factors with C-Reactive Protein and some haemostatic system components, analysing the newest knowledges yet under study. Therefore, I believe that the present issue can up to date researchers, physicians, and also students on the state of art of a subject that is continuously in growth.

References

[1] Smith C. C-reactive protein and asymmetric dimethylarginine: markers or mediators in cardiovascular disorders ? Curr Pharm Des 2007; 13(16): 1619-1629.

[2] Ferri C, Croce G, Cofini V, De Berardinis G, Grassi D, Casale R, et al. C-reactive protein. Interaction with the vascular endothelium and possible role in human atherosclerosis. Curr Pharm Des 2007; 13(16): 1631-1645.

[3] Kakafika AI, Liberopoulos EN, Mikhailidis DP. Fibrinogen : a predictor of vascular disease. Curr Pharm Des 2007; 13(16): 1647-1659.

[4] Leone A. Smoking, haemostatic factors, and cardiovascular risk. Curr Pharm Des 2007; 13(16): 1661-1667.

[5] Jagroop JA, Kakafika AI, Mikhailidis DP. Platelets and cardiovascular risk: an option for treatment. Curr Pharm Des 2007; 13(16): 1669-1683.

[6] Weyrich A, Cipollone F, Mezzetti A, Zimmerman G. Platelets in atherothrombosis: new and evolvine role. Curr Pharm Des 2007; 13(16): 1685-1691.

[7] Virdis A, Ghiadoni L, Plantinga Y, Taddei S, Salvetti A. C-reactive protein and hypertension: is there a causal relationship? Curr Pharm Des 2007; 13(16): 1693-1698.

[8] Balbarini A, Barsotti MC, Di Stefano R, Leone A, Santoni T. Circulating endothelial progenitor cells . Characterization, function and relationship with cardiovascular risk factors. Curr Pharm Des 2007; 13(16): 1699-1713.

[9] Iezzi A, Ferri C , Mezzetti A, Cipollone F. Cox-2: Friend or foe? Curr Pharm Des 2007; 13(16): 1715-1721.


Aurelio Leone, MD Chief
Former Director Department of Internal Medicine
City Hospitals Massa and Carrara, Italy
Consultant Cardiologist at the Cardio-thoracic Department
University of Pisa, Italy
Fellow of the Royal Society for Promotion of Health, UK
Member of the American Society of Hypertension, American
Society of Geriatric Cardiology, and World Heart Federation
Via Provinciale 27
19030 Castelnuovo Magra SSP
Italy


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C-Reactive Protein and Asymmetric Dimethylarginine: Markers or Mediators in Cardiovascular Disorders?
C.L. Smith

C-reactive protein (CRP) has received much attention as a cardiovascular risk factor and has been recommended to be used in screening to assist in predicting the occurrence of cardiovascular disorders. There are numerous association studies documenting changes in circulating CRP concentrations, there are, however, fewer studies providing evidence that CRP mediates the progression of cardiovascular pathologies. Elucidating the potential mechanisms for CRP has been confounded by recent reports that contaminants of CRP are partially responsible for observed effects.

In this review the use of CRP as a tool to predict cardiovascular disorders will be discussed alongside a more recently described cardio-vascular risk factor asymmetric dimethylarginine (ADMA). An endogenously occurring nitric oxide synthase inhibitor, ADMA, is formed by the action of protein arginine methyltransferases and subsequent proteolysis and it is metabolised in vivo by the dimethylarginine dimethylaminohydrolases (DDAH). The evidence available documenting the effects of CRP and ADMA, the regulatory mechanisms and the genetic influences, will be discussed in order to determine whether CRP and ADMA are mediators in the progression of cardiovascular disorders or merely useful biomarkers.


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C-Reactive Protein: Interaction with the Vascular Endothelium and Possible Role in Human Atherosclerosis
C. Ferri, G. Croce, V. Cofini, G. De Berardinis, D. Grassi, R. Casale, G. Properzi and G. Desideri

C-reactive protein (CRP) is the first acute phase protein that has been described in the literature. It is phylogenetically ancient and - with serum amyloid P - belongs to proteins named as “pentraxin”. After being considered a marker of acute inflammation for several decades and fruitfully used in clinical practice, CRP has been recently considered as a potential contributor to inflammatory diseases including atherosclerosis as well as a marker of cardiovascular risk. With regard to the first topic, inflammation is now believed to represent the underlying mechanism leading to the formation of human atheroma and favouring both the destabilization of vulnerable plaques and the formation of occlusive thrombi. In this regard, numerous studies indicated that modest changes in circulating CRP levels, as detected by highly sensitive methods, can be extremely useful in predicting cardiovascular and perhaps cerebrovascular diseases in apparently healthy individuals as well as in patients affected by atherosclerosis. Subjects manifesting with identical low density cholesterol and/or blood pressure levels have different rates of cardiovascular accidents on the basis of different circulating CRP concentrations. In addition, women with identical cardiovascular risk profiles developed more type 2 diabetes in the presence of higher circulating CRP levels and thereby are expected to display divergent cardiovascular prognosis. Therefore, even slight changes in circulating CRP concentrations – assuming that blood is collected appropriately and CRP is measured with correct methods – could help clinicians in defining individual cardiovascular risk.

In this review, we have firstly described the current understanding of the structure of CRP, its function, and interaction with the vascular endothelial cell. Then, we have discussed how to measure circulating CRP and the more recent findings on the suggested role of circulating CRP as a novel cardiovascular risk factor.


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Fibrinogen: A Predictor of Vascular Disease
A.I. Kakafika, E.N. Liberopoulos and D.P. Mikhailidis

Raised plasma fibrinogen levels are associated with an increased risk of vascular events. This may be mediated by adverse effects of fibrinogen on plasma viscosity, coagulation, platelet activity, inflammation and atherogenesis. However, there is as yet no drug that specifically lowers plasma fibrinogen levels on a long-term basis. Thus, we do not have intervention trials demonstrating that lowering plasma fibrinogen levels will result in a decreased risk of vascular events. However, such a trial may never happen unless a specific agent is discovered or designed.

Several drugs that are used in vascular disease prevention (e.g. lipid lowering agents and antihypertensives) may influence plasma fibrinogen levels. Whether such an additional effect accounts for variations in the benefit resulting from the use of different drugs within the same class remains to be established.

The debate continues as to whether fibrinogen is just a marker of vascular risk or whether lowering its circulating levels will result in a significant decrease in clinically relevant endpoints. Whatever the case, the measurement of plasma fibrinogen levels is likely to provide a more comprehensive estimation of risk.


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Smoking, Haemostatic Factors, and Cardiovascular Risk
A. Leone

There is a strong relationship between cigarette smoking and haemostatic parameters to increase the risk of cardiovascular events.

Smoking influences negatively coagulation-fibrinolysis cascade at any level, although it acts primarily on those pathways that are most important for an effective clot formation: endothelium, platelets, and fibrinogen.

Endothelial dysfunction is a main consequence of smoke compounds with significant changes in initiating physiologic coagulation proc-ess; platelet adhesiveness and aggregation increases as a result of smoking; finally, fibrinogen/fibrin framework strengthens clot thick-ness. Therefore, the whole coagulation cascade activates the thrombi formation pathway under smoking action. The risk of thrombotic cardiovascular events increases its frequency with more severe atherosclerotic alterations if compared to similar events in nonsmokers.

Changes in haemostatic factors produced by smoking appear to be related to female sex, especially for those women who use oral contra-ceptives. Thrombosis of coronary and cerebral arteries are found with a major incidence in young women who are users.

In conclusion, cigarette smoking modifies haemostatic parameters via thrombosis with consequently more rate of cardiovascular events.


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Platelets and Vascular Risk: An Option for Treatment
I.A. Jagroop, A.I. Kakafika and D.P. Mikhailidis

Epidemiological studies have linked platelet hyperactivity with an increased risk of vascular events. Even more convincing is the evidence from appropriately designed clinical trials showing that antiplatelet agents decrease the risk of vascular events (e.g. myocardial infarction, MI and stroke). These findings are compatible with the known thrombotic action of platelets.

A considerable limitation in platelet research is the absence of a reliable, universally accepted marker of platelet activity. Therefore, it is difficult to reliably identify the ‘high risk patient’ and/or evaluate the efficacy of any administered treatment other than by calculating event rates over a period of time.

This review will focus on the preventive aspects of antiplatelet intervention while also briefly considering the assessment of platelet hyperactivity and the mechanisms involved in platelet-induced thrombosis.


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Platelets in Atherothrombosis: New and Evolving Roles
A. Weyrich, F. Cipollone, A. Mezzetti and G. Zimmerman

The functional interplay of platelets with leukocytes and endothelial cells is critical both in physiological conditions, such as host defense, wound repair and tissue healing, and in pathological conditions, such as thrombotic and inflammatory diseases. The understanding of the specific molecular links underlying these cellular interactions and the functional changes that they induce could suggest new targets for pharmacological intervention. In this review, we summarize some of the newly-recognized aspects of interaction between platelets and monocytes, neutrophils and endothelial cells, that are relevant to all of the phases of atherosclerosis progression, since the early steps of atherogenesis to plaque rupture and thrombosis, the main causes of acute coronary syndromes.


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C-Reactive Protein and Hypertension: Is there A Causal Relationship?
A. Virdis, L. Ghiadoni, Y. Plantinga, S. Taddei and A. Salvetti

There is a large body of evidence indicating that inflammation plays a crucial role in all steps characterizing the atherosclerotic process. C-Reactive Protein is a circulating marker of inflammation which recently emerged as a powerful independent determinant of cardiovascular events. Hypertension is closely linked to inflammation. Experimental data and results from cross-sectional studies in humans indicate a relationship between CRP levels and blood pressure. In particular, CRP seems to be related with markers of arterial stiff-ness, thus suggesting a specific interaction between CRP and systolic blood pressure. However, such observational studies cannot provide any direct evidence for a cause-effect relation. Prospective studies are likely candidates to better define the putative causal relationship on this association. Available results from longitudinal studies are scanty, and do not allow to draw definitive conclusions. Moreover, prospective, placebo-controlled intervention trials documenting that reduction of CRP levels by pharmacological treatment might lead to a reduced risk to develop hypertension are not yet available. Without such crucial information, at the present time the causal connection between inflammation and blood pressure, although regarded as an intriguing possibility, remains undiscovered.


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Circulating Endothelial Progenitor Cells Characterization, Function and Relationship with Cardiovascular Risk Factors
A. Balbarini, M.C. Barsotti, R. Di Stefano, A. Leone and T. Santoni

Since the first description of putative progenitor endothelial cells mobilized from bone marrow by stimuli like ischemia and cytokines, several studies in animals have confirmed their role in neovascularization of ischemic organs. In ischemic myocardium endothelial progenitor cells can prevent cardiomyocyte apoptosis, reduce remodeling and improve cardiac function.

These observations led to the hypothesis of endothelial progenitor cells as possible cell-based therapy in patients by autologous transplantation in ischemic tissue or by improving peripheral circulating numbers with mobilization by cytokines.

Early trials, including a randomized one, suggest that the intracoronary autologous bone marrow cell transfer after myocardial infarction exerts at least short term functional benefits.

Since endothelial damage and dysfunction play a critical role in atherosclerosis disease, research interest was addressed to evaluate the role of progenitor endothelial cells in vascular endothelial layer maintenance. Opposing to local resident endothelial cells poor proliferate rate, progenitor endothelial cells regenerative capacity, homing and integration into blood vessels have been interpreted as a protective role of these cells in vascular homeostasis.

Indeed, the number and function of endothelial progenitor cells relate with the progression of atherosclerosis; the accumulation of cardiovascular risk factors or an increased overall risk are inversely associated with endothelial progenitor cells number and function.

Finally, recent studies have shown a role of progenitor cells numbers to predict cardiovascular events, raising endothelial progenitor cells to the podium of novel prognostic biomarker.


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COX-2: Friend or Foe?
A. Iezzi, C. Ferri, A. Mezzetti and F. Cipollone

It wasn't until 1990, when the existence of two different cyclooxygenases was hypothesized, based on the evidence that steroids inhibited the increase in COX activity induced by bacterial lipopolysaccharides in macrophages, without any effects on the basal production of prostaglandins or leukotrienes. The first isoform, COX-1 is responsible for the production of "housekeeping" prostaglandins critical to the maintenance of normal renal function, gastric mucosal integrity, platelet aggregation, and the autocrine response to circulating hormones. COX-2 on the other hand is an inducible enzyme, upregulated 20-fold in macrophages, monocytes, synoviocytes, chondrocytes, fibroblasts, osteoblasts and endothelial cells by various inflammatory stimuli and cytochines. Classical findings shown that the therapeutics effects of NSAIDs are largely dependent on COX-2 inhibition, whereas some undesirable side effects are bound to COX-1 blockade, such as gastrointestinal bleeding and renal failure. Therefore, agents that selectively inhibit COX-2 over COX-1 are desirable for the treatment of inflammation. However, since September 2004 reports of increased risk of thrombotic cardiovascular events had accumulated for coxibs, the COX-2 inhibitors. Our goal is to provide an overview of the relevant biology and pharmacology of this enzyme in atherosclerosis.