The Atherogene study showed that in populations with coronary heart disease the concentrations of E-selectin, ICAM-1 and VCAM-1 were greater in the patients who underwent cardiovascular events. Finally, the results obtained by Malik et al 10 in the British Regional Heart Study are not very encouraging regarding the prognostic value of adhesion molecules. Of the men enrolled in the study, samples were analyzed from men who developed coronary heart disease and who remained stable. Data obtained up to the present on the effect of treatment with lipid-lowering drugs on the plasma concentrations of different adhesion molecules are varied.
Jilma et al 12 analyzed circulating ICAM-1, VCAM-1, and E-selectin concentrations in 75 hypercholesterolemic patients who had been treated with 3 different statins for 3 months, and did not observe changes in plasma concentrations of the proteins analyzed. It should be pointed out that these studies were conducted in small populations; the results have recently been published of the AIM Atorvastatin on Inflammatory Markers study 13 which analyzed ICAM-1 plasma concentrations in subjects at high cardiovascular risk. Once leukocytes have adhered to the vascular wall, their entry into the interior is controlled by chemokines.
The 2 most numerous are alpha and beta chemokines. Alpha chemokines are chemotactic for neutrophils or lymphocytes, and include the interleukins IL.
Beta chemokines attract monocytes and lymphocytes, in addition to basophils and eosinophils, but do not attract neutrophils. Monocyte chemoattractant protein-1 MCP-1 belongs to this family.. Biasucci et al 15 demonstrated that patients with unstable angina who died, or presented AMI or refractory angina during hospitalization, at admission had higher IL-6 concentrations than in those who remained stable.
In another study on unstable angina, which included patients, IL-6 and CRP concentrations predicted the risk of coronary death during a month follow-up period and were additive to the value provided by markers of myocardial damage. The IL-6 values were independent predictors of mortality during month follow-up.
Furthermore, the patients who had high IL-6 concentrations were those who demonstrated improvement after invasive treatment, and thus IL-6 could be used to guide treatment in this population.. Monocyte Chemoattractant Protein This chemokine is the main one governing monocyte recruitment to tissues where there is an active inflammatory response, as is the case in atherosclerotic lesions.
Online Learning Catalog - American College of Cardiology
The diagnostic and prognostic value of soluble MCP-1 has been demonstrated in different studies. MCP-1 plasma concentrations have been associated with different cardiovascular risk factors, and with a greater risk of developing a cardiovascular event in the future. Our group has demonstrated that treatment with atorvastatin only or in combination with amlodipine reduces MCP-1 concentrations in patients with carotid atherosclerosis. Without doubt, CRP is the most well-known inflammatory marker.
Regardless of the ability of CRP to predict risk in primary and secondary prevention, interest in CRP has increased since statins can reduce CRP concentrations independently of their lipid-lowering effect. In any case, great debate continues on its potential use in clinical practice. Lipoprotein-Associated Phospholipase A2. Lipoprotein-associated phospholipase A2 Lp-PLA2 is a calcium-independent lipase produced by leukocytes and is associated with circulating LDL and macrophages on atheromatous plaque.
Together with CRP, it is the most thoroughly studied predictor of cardiovascular risk. More than 25 prospective epidemiological studies have been published on Lp-PLA2 both in primary and secondary prevention. These clinical trials have usually demonstrated strong correlations between circulating Lp-PLA2 concentrations and the increased risk of cardiovascular events, even after multivariable adjustment for traditional risk factors. Lipoprotein-associated phospholipase A2 has also created great interest as a therapeutic target in coronary heart disease. It is found in high concentrations in the lipid core of inflammatory plaques and is produced by the inflammatory cells in the lesion or transported by LDL particles.
It acts on oxidized phosphatidylcholine found in the external part of oxidized LDL to generate lysophosphatidylcholine and oxidized fatty acids. These 2 bioactive lipid products stimulate lipid core expansion and thinning of the fibrous cap. The selective inhibition of Lp-PLA2, through treatment with darapladib, inhibited the development of advanced coronary atherosclerotic lesions in an experimental model.
The imbalance between the synthesis and degradation of the extracellular matrix is a key event in the weakening and rupture of advanced atherosclerotic plaques. Although death by apoptosis of vascular smooth muscle cells seems to be the main mechanism involved in reducing the synthesis of matrix components, increased degradation has been associated with increases in the concentrations and activity of various proteolytic enzymes.
Of these enzymes, the metalloproteinases MMP have been the most studied.. Most of the risk factors for atherosclerotic disease have been associated with an increase in the concentrations of various circulating MMP, including, among others, hypertension 42 and diabetes mellitus. Among the different therapeutic strategies used in atherosclerosis there are 2 which can modulate MMP concentrations: the administration of thrombolytics and of statins. The presence of these immuno-inflammatory-proteolytic processes in atherosclerotic plaque leads to destabilization, rupture and the consequent formation of thrombus, which forms the basis of the most severe clinical consequences of atherosclerosis.
This normally involves a plaque that only slightly blocks the vessel, contains fat and, upon rupture, leads to the lipid core—rich in tissue factor—coming into contact with the bloodstream, causing the formation of a thrombus that impedes blood flow.. An increase in soluble CD40L predicts a greater risk of cardiovascular events in healthy women. Thus, it is possible that in healthy women soluble CD40L can identify a group at special risk of vascular events, but not the majority..
In the first place, it was found that patients in the placebo group with high CD40L concentrations had an increased risk of death or non-fatal heart attack during the following 6 months. Secondly, the predictive value of CD40L was independent of troponin T concentrations—even when the values of this marker were elevated—since the CD40L values continued to have prognostic value.
It has been demonstrated that treatment with atorvastatin for 8 weeks reduces CD40L expression on blood platelets in hypercholesterolemic patients. There are 2 possible approaches to the search for new biomarkers.
Modern peptide biomarkers and echocardiography in cardiac healthy haemodialysis patients
The first is a classic approach based on the selection of proteins involved in the pathophysiology of atherothrombosis, like the examples reviewed in the first part of this article. In the second approach, which uses high-performance techniques such as proteomics, there is no need for prior knowledge of the proteins or of the function that they may perform in disease.
Using this approach, we can compare a patient's fluids or tissues with those of a healthy subject and, via tracing, see which proteins are expressed differently in either sample. This generates lists of proteins potentially involved in this disease, among which we should select those whose function or properties indicate that they have the potential for being good biomarkers..
The concentrations of sFasL are elevated in patients with heart failure, AMI, or unstable angina, which are acute situations in which inflammatory cells are highly activated and could increase the production of this protein. In contrast, in chronic situations, it has been observed that patients with familial combined hyperlipidemia or carotid atherosclerosis present striking reductions in circulating sFasL concentrations. It has been proposed that FasL expression in some tissues contributes to a state of immune privilege that prevents inflammatory cell infiltration, since these cells express its receptor and, as a result, would undergo apoptosis when coming into contact with the tissue.
In this regard, it has been demonstrated that FasL is produced in endothelial cells in normal circumstances and its expression can negatively regulate cell extravasation. Our hypothesis is that the endothelial dysfunction that occurs in these patients could be the reason for these findings, probably due to reduced endothelial synthesis or reduced release into the blood Figure 3.
To this end, we analyzed concentrations of sFasL in patients with coronary heart disease in whom the vasodilator response to reactive hyperemia was assessed as a marker of endothelial function. Note that there is a linear relationship between sFasL concentrations and reactive hyperemia, but not with blood flow in response to nitroglycerin an endothelium-independent response , which indicates that sFasL could be a marker of endothelial function in patients with coronary heart disease.
Figure 3. The Fas ligand FasL , a potential biomarker of endothelial dysfunction. FasL produces and releases endothelial cells in normal circumstances and its expression can negatively regulate cell extravasation by inducing apoptosis in leukocytes. When the endothelium is dysfunctional, different proinflammatory stimuli can reduce FasL expression and release by endothelial cells, which facilitates the entry of inflammatory cells during the early stages of atherosclerotic lesion development.. A reduction was observed in sFasL concentrations and an increase in sFas concentrations in patients at high cardiovascular risk, which could indicate that both proteins could be early markers of vascular injury.
Unfortunately, the study was not designed to assess cardiovascular events due to the short follow-up time, which means that the predictive value of sFas and sFasL should be tested in future studies.
The complex nature of the atherothrombotic process calls for the development of new technologies to help in the discovery of new mediators involved in this disease. Although genomics and proteomics have not been reviewed here due to limitations of space, they could be vital tools for identifying the genes and proteins that confer greater predisposition to cardiovascular events.
- The Village Rector.
- Amazing Series for Kids: Discover Cats Picture Book.
- Diamonds To Die For.
Within this approach, it is of importance to explicitly define clinical issues in order to obtain biomarkers specific to the disease in question Figure Figure 4. How to identify a biomarker..
Proteomic Approach to the Search for New Biomarkers. Two examples of new potential biomarkers obtained through proteomic techniques are detailed below.. Heat shock proteins HSP are a family of proteins that are present in most cells. Heat shock proteins act as intra-cellular chaperones assisting in establishing the correct conformation of proteins, as well as the translocation of oligomers, but they also aid in the elimination of irreversibly damaged proteins.
On the other hand, they can be secreted and detected in plasma. In different cardiovascular diseases, it has been found that HSP expression can be modulated both in the lesion and in plasma. Thus, HSP60 can be a marker of atherosclerosis. Subsequently, it has been observed that the increase in HSP70 concentrations is associated with less risk of coronary heart disease and fewer affected vessels.
A proteomic approach has identified HSP27 as a protein that is produced in great quantities by healthy arteries and whose production decreases to almost undetectable concentrations as the complexity of atherosclerotic plaque increases. Subsequently, a study was conducted which assessed HSP27 concentrations in a group of patients with carotid atherosclerosis and in healthy subjects of the same age and sex. Circulating HSP27 concentrations were significantly reduced in the experimental group compared to the control group 84 Figure 5.
Although these preliminary data should be validated in a broader group of patients, and in various stages of cardiovascular disease, they indicate that low HPS27 concentrations could serve as a diagnostic marker of advanced atherosclerotic disease. On the other hand, its possible prognostic value has only been tested in a study which compared baseline HSP27 concentrations among women in the Women's Health Study who developed cardiovascular events over a 6-year follow-up period and among women who did not develop them.
This prospective study found that the baseline HSP27 concentrations were not associated with the development of cardiovascular events. Figure 5. HSP27, a potential diagnostic biomarker of atherosclerosis. By permission of Circulation. These cytokines are involved in multiple biological responses, such as inflammation, the immune response and tissue repair.
Tumor necrosis factor-like weak inducer of apoptosis is widely expressed in different tissues, such as the pancreas, intestine, heart, brain, lung, ovary, and skeletal muscle, and to a lesser extent in the liver and kidney. Finally, sTWEAK demonstrated an inverse correlation with intima-media thickness in asymptomatic patients, which indicates that this protein could be a marker of subclinical atherosclerosis Figure 6.