C-Reactive
Protein, Fibrinogen, and Cardiovascular Disease Prediction
Abstract
In
an endeavor to enhance cardiovascular risk prediction, substantial interest has
been aimed at CRP or C-reactive protein, a good marker of inflammation[1].
This is so because this unique protein has been included in diverse potential
epidemiological studies in order to foretell stroke, peripheral arterial
disease, incident myocardial infarction, as also abrupt cardiac death. CRP
levels can also predict the risk of those who are going through percutaneous
angioplasty, recurrent ischemia, those admitted to emergency rooms suffering
from acute coronary syndromes as well as the incident of demise among people with
stable/unstable angina. This decidedly dependable clinical information is duly supported
by profuse experimental and laboratory evidence that amply demonstrate that
atherothrombosis, apart from being an ailment of lipid accumulation,
characterizes a chronic inflammatory process. In the context of clinical
application, C-reactive protein appears be a more potent predictor of most cardiovascular
events than the conventional LDL cholesterol, thereby adding prognostic data at
every level of calculated Framingham Risk as well as the metabolic syndrome. By
means of extensively available high-sensitivity assays, C-reactive protein levels
of <1, 1-3, along with >3 mg/L, that are in accordance with low, moderate,
and high risk groups for all future cardiovascular events. Individuals with LDL
cholesterol lower than 130 mg/dL and who have CRP levels of >3 mg/L embody a
high-risk group that is frequently missed in clinical practice. Adding CRP to
standard cholesterol appraisal might thus supply an uncomplicated and low-cost
method in order to advance global risk prediction and observance of preventive
approaches.
Fibrinogen
Fibrinogen
is considered to be a significant, self-determining risk factor in the instance
of cardiovascular disease[2]. This
suggests that an increase in the dynamic presence of fibrinogen might be a
conduit through which the accompanying risk factors apply their undue effect.
There are various mechanisms by which this substance might enhance cardiovascular
risk. Firstly it does so, by binding expressly to activate platelets by means
of glycoprotein IIb /IIIa, thus promoting platelet aggregation. Secondly, elevated
levels of fibrinogen help promote the formation of fibrin. Thirdly, the
substance is a dynamic contributor to factors such as plasma viscosity.
Finally, fibrinogen remains an acute-phase reactant that becomes enhanced in
inflammatory states.
Background
There
is ever increasing debates going on concerning the value of evaluating levels
of CRP or C-reactive protein, as also many other soluble biomarkers of
inflammation in order to predict the initial cardiovascular events. Several
learned societies and academic journals came forward to discuss the topic. As
early as 2003, the American Heart Association and the Centers for Disease
Control and Prevention arrived at the joint conclusion that CRP can be used at
a physician’s discretion, as a component of an international evaluation
cardiovascular risk.
In
2009, the Canadian Cardiovascular Society advocated CRP appraisal in those
patients who are at “intermediate risk,” a term that was defined as the
envisaged risk of any cardiovascular event, along the ensuing 10 years, of 10
percent to fewer than 20 percent.
In
the same year, the medicine practice guidelines issued by the National Academy
of Clinical Biochemistry Laboratory came to the conclusion that measurement of
the various CRP levels can come handy in the stratification of those patients
who are at intermediate risk of a cardiovascular event, even though all
available evidence concerning the utility of levels of fibrinogen as also some
other biomarkers of inflammation was deemed to be inconclusive. It is hoped
that more guidelines concerning those biomarkers should soon emerge.
There
is a correlation between fibrinogens and C-reactive proteins on the one hand
and cardiovascular situations on the other. This study is aimed at comprehending
the processes that make fibrinogens and C-reactive proteins impinge on Cardiac
syndromes.
Introduction
An
intrinsically disordered protein or IDP is a type of protein, lacking in a well
ordered three-dimensional structure[3]. IDPs
generally cover a whole series of states from wholly unstructured to partly
structured, including (pre-)molten globules, random coils, and big multi-domain
proteins united by flexible linkers. They contain significant kinds of protein
along with fibrous, globular, as also membrane proteins[4].
The
discovery of the unique IDPs has defied the conventional protein structure
paradigm: the function of protein function remains dependent on a set
three-dimensional structure. This paradigm has been threatened by the
increasing evidence derived from several disciplines of structural biology,
implying that that protein dynamics might be highly pertinent for like systems.
In spite of their being deficient in of stable structure, IDPs are an extensive
and functionally significant type of proteins. In certain situations, IDPs can
take on a fixed three-dimensional structure following a binding with other
macromolecules. On the whole, IDPs are unlike structured proteins in various
ways and be likely to possess specific properties in terms of structure,
evolution, function, sequence, interactions, and regulation[5].
Method
We
made an analysis of data from 52 potential studies, consisting of an incredible
246,669 participants belonging to various nationalities and ages, all of them
wholly free from any history of cardiovascular disease, for the investigation
of the value of appending fibrinogen or CRP levels to traditional risk elements
to predict cardiovascular risk. We computed the measures of discrimination as
also reclassification throughout the follow-up periods and created models to
represent the clinical implications of the commencement of statin therapy
following the appraisal of fibrinogen or CRP[6].
Findings
By
adding the information on high-density lipoprotein cholesterol to a predictive
model for CVD that consisted of sex, age, smoking status, history of diabetes, blood
pressure as well as total cholesterol level, there was an increase in the
C-index, which is a degree of risk discrimination, by an amount of 0.0050. Adding
this model of information on fibrinogen or CRP further, again n amplified the
C-index by 0.0027 and 0.0039 respectively to P<0.001, and provided a net
reclassification improvement of 0.83% and 1.52% respectively, for the entire predicted
10 year risk categories comprising of "low" amounting to <10%),
"intermediate" to 10% to <20%, as also "high" to ≥20%,
with P<0.02 for both the comparisons. We anticipated that among 100,000
grown-ups aged 40 years or more, 15,025 individuals would primarily be
classified as that of at intermediate risk for a cardiovascular event, provided
only traditional risk factors were used to compute the risk. Presupposing that
statin therapy would be commenced in line with Adult Treatment Panel III
guidelines, by virtue of adding targeted evaluation of fibrinogen or CRP levels
in the outstanding participants numbering 13,199, who are at intermediate risk,
could help in the prevention of about 30 more cardiovascular events for duration
of 10 years[7].
Conclusion
In
a research study of persons without any known cardiovascular disease, it was
estimated that under the present treatment guidelines, estimation of the
fibrinogen or CRP level of those belong to the category of intermediate risk
for a cardiovascular event can help in the prevention of one extra event for a
duration of 10 years for each 400 - 500 individuals screened[8].
Importance of Intrinsic Disorder for
Understanding CVD.
Relevant data indicates that
intrinsic disorder remains extremely profuse in CVD-related proteins. Moreover,
flexibility can have a vital role to play in the function of a few of these
proteins. How general can these observations be? Intrinsically disordered
proteins can perform various vital biological functions [9], as they are rigorously
involved in the matter of cell signaling[10], recognition, and nucleic
acid and protein−protein interactions [11]. The extreme flexibility
related to intrinsic disorder accords proteins numerous functional benefits
over globular proteins, having definite three-dimensional structures. Two of these
disorder-related functional advantages are extremely vital for signaling
proteins, as these have high specificity along with low affinity as also binding
diversity[12].
The primary property determines an extremely specific and rapid response of a
signaling protein to a specified stimulus, while the second one has the responsibility
of binding the diversity of proteins engaged in the wide cascade of
protein−protein interactions. It has been theorize d that the measure of
intrinsic disorder in extremely connected proteins or hubs must correlate with
the number of interacting partners. This assumption was substantiated by the
analysis of the disorder prediction for various hubs. Moreover, the performance
of cell-signaling proteins is generally acknowledged to be in harmony with
several post-translational modifications that were demonstrated to occur frequently
in disordered regions [13]. For instance, it was shown
that factors such as sequence complexity, amino acid compositions,
hydrophobicity, charge, as well as other sequence attributes of realms adjoining
the phosphorylation, remain analogous to those of intrinsically disordered
protein areas. By depending on these observations, a unique web-based tool to predict
protein phosphorylation sites, termed DISPHOS or disorder-enhanced
phosphorylation predictor, came to be developed[14].
Another significant
benefit of intrinsic disorder is that the flexible regions and/or proteins are
subjected to rapid proteolytic digestion. It has been demonstrated that
disordered regions are actually ∼106-fold more swiftly digested than is
the case with ordered regions, as well as a local unfolding of ∼13 residues adjoining the scissile bond is
essential for protease binding. This is critical for all signaling proteins, because
every cellular signaling process requires finely tuned control and quick removal
of certain proteins in the cell. Disordered regions probably bear the signals
for the machinery of proteolytic degrading as a primary part of their general regulatory
role.
The affiliation between
disorder content and conformational stability remain a significant question. Wholly
disordered proteins lack an ordered structure and this renders them somewhat
insensitive to increases in temperature and opposed to heat-induced
aggregation. This is so because the elevated content of charged amino acid and hydrophilic
residues render unstructured proteins soluble at high temperatures. In the same
way, several completely disordered proteins have enhanced stability toward perchloric
acid and richloroacetic treatment. Conversely, it is anticipated that a
semifolded protein, having an extended disordered region can have diminished
conformational stability as compared
to the fully ordered protein of a like size. Notably, the folding state and stability
of these inherently disordered proteins can depend on the incidence of explicit
binding partners.
Consideration of
intrinsic disorder remains decisive for the understanding of alternative
splicing[15], an essentially
biological process, occurring at the time of the maturation step of a pre-mRNA,
permitting the creation of diverse mature mRNA variants stemming from an
exclusive transcription unit. Alternative splicing is a crucial mechanism in
the production of a lot of protein and mRNA isoforms, out of a few genes. This renders
complex the multicellular eukaryotes by enhancing proteome size and protein
diversity in spite of the comparatively small number of these genes. Actually, between
35% and 60% of all human genes are projected to produce protein isoforms
through alternatively spliced mRNA [16]. Recent research has emphasized
the significance of alternative splicing in the form of a regulatory process, having
a high frequency in signaling and regulatory proteins. Besides, it has been
revealed that alternative splicing is frequently linked to wholly and partially
disordered protein regions, implying that the mapping of alternatively spliced
segments with regions of intrinsic protein disorder can enable functional as
well as regulatory diversity, at the same time evading structural catastrophe. Significantly,
there is a correlation between problematic alternative splicing as also the development
of various human ailments. A descriptive instance of a disease linked to
alternative splicing is problematic postnatal heart remodeling. Lately, an
indispensable splicing factor, like ASF/SF2, has been acknowledged as a principal
constituent of the program that regulates a rather restricted group of
tissue-specific alternative splicing events, while engaged in heart remodeling.
Cardiomyocytes lacking in ASF/SF2 exhibit an unpredicted hypercontraction
phenotype because of a flaw in the postnatal splicing switch of Ca2+/calmodulin-dependent
kinase IIδ (CaMKIIδ) transcript. This failure results in mistargeting of the
kinase to sarcolemmal membranes, causing severe excitation−contraction coupling
defects [17].
This shortcoming causes
the wrong targeting of the kinase to sarcolemmal membranes, resulting in defective
in the process of extreme excitation−contraction coupling.
Intrinsic Disorder and Discovery of
Anti-CVD Drugs.
The likelihood of disrupting
the action of CVD-related proteins via the modulation of protein−protein
interactions affords a particularly striking opportunity, to develop fresh drugs
in the obstruction of CVD. Previously, the design pattern for all those drugs that
target disrupting protein−protein interactions remained sorely unsuccessful, because
of difficulties in ascertaining drugs that can bind themselves to rigid protein
surfaces[18]. Still, the success in
developing short peptides as also small
molecules with the ability to block the p53−Mdm2 interaction, opens up the possible
launch of a new era, termed the “signaling-modulation era”, during which drugs
will be aiming at protein−protein interactions. The creation of the p53−Mdm2
complex, involving a disorder-to-order transformation in the disordered
N-terminal tail of p53, forming as it were the helix that can bind Mdm2. This study
amply demonstrates that discovering small molecules that target protein regions
ordinarily bound by disordered proteins is possible. Another instance of involving
a disorder-to-order transformation in disease-related proteins is the
interaction of thrombin with hirudin[19]. Recent research
demonstrated that the disorder features of fibrinogen peptides can result in anticoagulation
drug design. Information presented in our study underlines the pivotal role of
intrinsic disorder for structure as well as the function of those proteins
involved actively in CVD. This knowledge is bound to facilitate researchers in
the exploration of the potentiality of aiming at all disorder-based
protein−protein interactions of every disordered protein that is linked to CVD.
Recently we sought to recognize the sequence characteristics of protein−protein
interactions that remain readily blockable using little molecule drugs. The
work has caused the discovery of potentially druggable sites in their thousands[20], that include 198 that
assists in CVD-associated protein−protein interactions.
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