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Cardiovascular diseases: Traditional and non-traditional risk factors

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DOI: 10.5455/jmas.228597

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 J Med Allied Sci 2016; 6 (2): 46-51 Journal of
www.jmas.in Medical &
Print ISSN: 2231 1696 Online ISSN: 2231 170X Allied Sciences

Review
Cardiovascular diseases: Traditional and non-
traditional risk factors
Chittakath Shaima, Puthamohan Vinayaga Moorthi, Naser Kutty Shaheen
Department of Human Genetics and Molecular Biology, School of Life Sciences, Bharathiar University,
Coimbatore-641046, Tamil Nadu, India.
Article history: Abstract
Received 19 May 2016 Cardiovascular disease (CVD) is responsible for more number of
Revised 12 July 2016
deaths worldwide. The muscles and vessels of heart and blood trans-
Accepted 15 July 2016
Early online 29 July 2016 porting roads become vulnerable portion in most of the CVD. The role
Print 31 July 2016 of hypertension and cholesterols of different density triglycerides in in-
duction and progression of cardiovascular disease is discussed in this
Corresponding author present review. Besides this the potential biomarkers such as
Puthamohan Vinayaga Moorthi homocysteine, fibrinogen, D-dimer and thrombin/anti-thrombin III com-
Assistant Professor, plex, interleukin and serum amyloid in prognosis is also discussed in
Department of Human Genetics and
this review.
Molecular Biology,
School of Life Sciences,
Bharathiar University, Key words: Cardiovascular disease, Diabetes, Fibrinogen, HDL, LDL
Coimbatore-641046,
Tamil Nadu, India. DOI: 10.5455/jmas.228597
Phone: +91-9994809189
Email: [email protected]
© 2016 Deccan College of Medical Sciences. All rights reserved.

ardiovascular diseases (CVD) which mainly Traditional risk factors

C include coronary heart disease (CHD),

stroke, rheumatic heart disease (RHD) and
cardiomyopathy represent the leading cause of
1 th
Although earliest research has recognized hyper-
tension, diabetes and hypercholesterolemia as
traditional CVD risk factors, several researchers
death worldwide . In the early 20 century, CVD
have reported their absence in a considerable por-
was responsible for less than 10% of all deaths
tion of individuals experience clinical vascular
worldwide, but it increased to 30% by 2001. Coun-
events. Indeed, up to half of those having their first
tries like low and middle-income have 80% deaths
clinical vascular events does not have traditional
due to CVD. By 2020, CVD will become the lead- 6
2 CVD risk factors . However, these findings may not
ing cause of death and disability in low and mid-
be relevant to all populations, researchers from the
dle-income countries. In a year, mortality of CVD
3 FHS report that 50% of the patients with CHD had
accounts ~ 9% . CVD includes a wide range of
levels of total cholesterol (TC) ≤240 mg/dl and 20%
disorders which includes diseases of the cardiac 7
had TC <200 mg/dl .
muscle and of the vascular systems. Potential risk
factors for CVD include hypertension, tobacco use, Data from the Women’s Health Study (WHS) con-
physical inactivity, elevated low-density lipoprotein firmed those three quarters of coronary events
cholesterol, diabetes and a cluster of interrelated happen in 27,939 women without a high level of
4
metabolic risk factors . Framingham Heart Study in LDL cholesterol (<160 mg/dl) and 45% happen in
8
1961 was the first to introduce the concept of risk women with normal LDL cholesterol (<130 mg/dl) .
factors which links the presence of high cholester- When numerous large studies of CVD were re-
ol, tobacco usage, hypertension and diabetes viewed, as one would expect, most individuals had
5 9
mellitus to future CVD . Mostly CVDs are due to one or more traditional risk factors . Conversely,
atherosclerosis as well as due to infections. one fifth had none of the traditional risk factors. In

46
Shaima C et al Traditional and non-traditional markers of CVD

addition, among cohort individuals who did not suf- a curvilinear relation between TC and age-adjusted
fered CHD, the rates of traditional cardiovascular CHD death rate; in MRFIT screeners with a TC
10
risk factors were also relatively high . Given these level of ≥240 mg/dL, relative risk (RR) for CHD,
findings, new research has focused on ways of
compared with those with TC <182 mg/dL, the
enhancing our ability to predict CVD. However, 22
many of these show promise and most widely used death rate was 3.4 . Conversely, except TC, there
in routine clinical practice. are factors influencing the risk of CHD risk was
clearly established by studies of 25 years of follow-
Hypertension and cardiovascular disease 23
up in the Seven Countries Study (SCS) , in which
In its Sixth Report, the Joint National Committee on a dose-response association between TC and
Prevention, Detection, Evaluation, and Treatment CHD mortality rate was observed.
of High Blood Pressure (1997) defines categorical
hypertension as a BP ≥140 mmHg systolic or ≥90 Studies across different populations demonstrate
mmHg diastolic or current use of antihypertensive that those with higher cholesterol levels have more
drugs. Several observational studies have con- atherosclerosis and CHD than do those who hav-
firmed clearly a powerful relationship between high ing lower levels (Keys et al., 1984). The positive
11-13
BP and CHD . This relationship holds for both association between proportion of serum choles-
men and women and younger and older persons. terol and onset of first or consequent CHD attack,
Occasionally those with high BP are at higher risk due to elevated LDL cholesterol, was observed;
14 24
of CHD . the higher the level, the greater the risk . Prospec-
tive data recommended that the risk of CHD at
Diabetes and cardiovascular disease
lower cholesterol levels and this evident has dis-
24,25
Risk for all forms of CVD, is increased significantly appeared in larger studies . Population with
in patients with type 1 and type 2 diabetes melli- very low serum cholesterol e.g. TC <150 mg/dL (or
15,16
tus . The mortality rate in non-diabetic patients LDL cholesterol <100 mg/dL) witness the almost
26,27
was less compared to diabetic patients who expe- absence of clinical CHD throughout the life .
17,18
rienced CHD . Hyperglycemia is considered to
The association between the elevated LDL choles-
be the potential risk factor while it is not dependant
terol to the onset of CHD observed to be a multi-
on the normally observed characters in diabetics 28
step process . Atherogenesis, the fatty streak,
like obesity and dyslipidemia. Good glycemic con-
having macrophages filled with cholesterol, is the
trol decreases risk for microvascular complications
first stage and most of them derived from LDL cho-
of diabetes. However, in diabetic patients, signifi-
lesterol. The fibrous plaques, scar tissue over lipid
cant control of glucose has not been reducing the
rich core, are the second stage. Other risk factors
macrovascular disease (CHD), although a trend
19 also contribute to plaque growth. The third stage is
toward benefit has been observed .
demonstrated the onset of plagues, prone to rup-
Total cholesterol, low-density lipoprotein cholester- ture and luminal thrombosis formation, of unstable.
ol and cardiovascular disease Plaque rupture is responsible for most acute coro-
29,30
nary syndromes (ACS) .
Cholesterol is synthesized almost in all cells and
Triglycerides, very low-density lipoprotein choles-
considerable amounts of it can be absorbed from
terol and cardiovascular disease
the diet. According to the lipid hypothesis, unusual-
ly high cholesterol levels (hypercholesterolemia), Triglyceride (TG) is an ester formed from a glycerol
or higher concentrations of LDL cholesterol have molecule, provided OH group each with and make
20
been recognized as principle lipid risk factors . up the majority of fats, which was later properly
Various studies have confirmed that blood TC lev- utilized by digestion. Lipids cannot be absorbed by
els have an exponential role on cardiovascular and the duodenum in TG form and it is absorbed as
total mortality, with the association more evident in fatty acids, monoglycerides and some diglycerides,
younger subjects. In old age people, the effect of once the TG have been digested. In the human
21
higher cholesterol on health is indeed larger . body, high levels of TG in the bloodstream have
been linked to atherosclerosis and CHD.
Several studies have consistently confirmed that
CHD risk and TC had a dose-response relation- Several observational studies and analysis pub-
ship. The Multiple Risk Factor Intervention Trial lished in the earlier years largely support TG as an
(MRFIT) screened >300,000 men and established independent risk factor for CHD. These studies

J Med Allied Sci 2016;6(2) 47

Shaima C et al Traditional and non-traditional markers of CVD

44
have been performed in populations over a wide increase in CHD risk . Low HDL cholesterol,
spectrum of ages in a number of countries with based on epidemiology studies, to be an inde-
31-34
quite different rates of CVD . Traditionally, CHD pendent risk factor for CHD and it holds after cor-
events due to elevated TG were predicted in rection for other risk variables in multivariate anal-
univariate analysis, after adjustment for other co- ysis.
variates, including plasma glucose and HDL cho- 45,46
In fact, in prospective studies , HDL cholesterol
lesterol, to which it is strongly and inversely corre-
35 usually the risk factor of CHD risk having high cor-
lated . Yet, even after adjustment for HDL choles-
relation with CHD risk. Adult Treatment Panel II
terol, detailed assessment of population-based
(ATP II) at <35 mg/dL were noticed as a low HDL
prospective studies has disclosed an independent
36 cholesterol, one of several major risk factors used
effect of TG on CHD events . Coupled with the
to modify the therapeutic goal for LDL cholesterol.
knowledge that combined hyperlipidemia promotes
The definition of low-HDL cholesterol was set to be
CHD to a significantly greater extent than either
37 the same for both genders because the level of
high LDL cholesterol or TG alone .
HDL cholesterol would impart the same risk for
Very low-density lipoprotein (VLDL) cholesterol is a men and women.
type of lipoprotein formed by the liver, which ena-
Non-traditional risk markers
ble movement of fats and cholesterol within blood
stream. It is accumulated in the liver from choles- The epidemiological and basic science search for
terol and apolipoproteins, which converted in the better understanding of the etiology of CVD has
bloodstream to LDL cholesterol. VLDL cholesterol produced numerous serum markers as candidates
transports endogenous products (such as TG, for representing “nontraditional” risk. Several are
phospholipids, cholesterol and cholesteryl esters) part of the progression of inflammation - a process,
where chylomicrons transport exogenous (dietary) now understood to be central to atherosclerotic
47
products. disease . Candidates have included
homocysteine, plasminogen activator inhibitor-1
The most likely candidates for atherogenic TG-rich
(PAI-1), fibrinogen, D-dimer and throm-
lipoproteins (TGRLP) are remnant lipoproteins.
bin/antithrombin III complex; and various inflamma-
These lipoproteins include small VLDL cholesterol
tory markers such as CRP, interleukin (IL), serum
and lipoproteins of intermediate-density i.e., IDL.
amyloid A (SAA), MMP and adhesion molecule.
The atherogenicity of remnants was well supported
38-40 However, many of these markers show promise,
by several reviews . In several clinical studies
most are not used in routine clinical practice and
elevation as well as their specific identification of
the predictive power of many has not been con-
remnants was noticed to be strong predictors of
41-42 firmed.
CHD .
Homocysteine
High-density lipoprotein cholesterol and cardiovas-
48,49
cular disease It was clearly understood from the literatures
that the role of homocysteine as oxidative stress
HDL cholesterol is one of the 5 major groups of
indicator. As a mediator of one carbon metabolism,
lipoproteins cholesterol, which enable lipids like 50-52
homocysteine, levels are associated with CVD .
cholesterol and TG to be transported within the 53
It was suggested (Humphrey et al., 2008) that,
water based blood stream. In healthy persons,
the level of homocysteine moderately increase the
about thirty percent of blood cholesterol is carried 54
risk of CVD by 20%. Ueland et al. and Van
by HDL cholesterol. An increased level of HDL 55
Guldener et al. reported that, the one type of
cholesterol protect against CVD while lowering
CVDs, like stroke and deep vein thrombosis can be
which cause enhanced heart disease risk. When
reduced by reducing the level of homocysteine by
measuring cholesterol, some contained in HDL
3-5 mol/L in serum.
particles is considered as guardians of the cardio-
vascular health of the body, in contrast to "bad” Plasminogen activator inhibitor-1 (PAI-1)
LDL cholesterol. 56
PAI-1 is the key fibrinolysis regulator. Jugo et al.
Strong epidemiological evidence links low serum based on the bivariate analysis, stated that, the
43,44
HDL to increased CHD morbidity and mortality . PAI-1 was directly correlated with carotid intima-
High HDL cholesterol levels conversely convey media thickness, BP, Body Mass Index (BMI), LDL
reduced risk. Various epidemiological data taken and total cholesterol, glomerular filtration and tri-
57
as a whole suggest that a 1 percent decrease in glycerides. Zhuang et al. reported that, the pa-
HDL cholesterol is associated with a 2–3 percent tients with acute ischemic stroke had significant

J Med Allied Sci 2016;6(2) 48

Shaima C et al Traditional and non-traditional markers of CVD

amount of t-PA, while level of PAI-1 was reduced tobacco use, physical inactivity, elevated low-
significantly. Existence of negative correlation be- density lipoprotein cholesterol, diabetes and a clus-
4
tween t-PA and PAI-1 was revealed and significant ter of interrelated metabolic risk factors . However,
difference in activities of t-PA and PAI-1 was ob- many patients never acquired adequate control
served in control group, acute, convalescent and over the CVD risk factors even when these factors
58
chronic groups. Tofler et al. revealed that, those have been identified. Besides the growing preva-
with CVD have higher level of PAI-1 (29.1 ng/ml) lence of obesity and type 2 diabetes mellitus (Type
compared to those without (22.1 ng/ml) CVD. It -2 DM) threatens to decline the improvements in
was also observed from his experiment that, an CVD that have been achieved. The increased inci-
antigen level of PAI-1 and t-PA was in strong linear dence of obesity has contributed to significant in-
relationship with CVD incidence. crease in the prevalence of other important CVD
risk factors, including hypertension, dyslipidemia,
Fibrinogen 4
insulin resistance, and type 2 DM . Various studies
Fibrinogen (Fg), the precursor of fibrin, coagulation have confirmed that blood cholesterol are primarily
factor described first in 1836 by Buchanan. The important component that leads to CVD and its
hematological changes such as increase in viscosi- associated mortality evidenced in younger sub-
ty of plasma, aggregation of erythrocytes, jects. A high level of HDL cholesterol seems to
thrombogenesis of platelets are due to increase in protect against CVD and low HDL cholesterol lev-
59 60
level of Fg . Meade et al. , based on the epide- els increase the risk for heart disease. Non-
miological studies, stated that the risk of CVD such traditional risk markers includes homocysteine,
as ischaemic heart disease, thromboembolism and coagulation markers such as plasminogen activa-
stroke increase with respect to the increase in con- tor inhibitor-1 (PAI-1), fibrinogen, D-dimer and
centration of plasma Fg. thrombin/anti-thrombin III complex; and various
inflammatory markers such as CRP, interleukin
D-dimer
(IL), serum amyloid A (SAA), MMP and adhesion
The fibrin degradation marker, D-dimer, one of the molecule. Pharmacologic therapies are now avail-
61
important marker associated with CVD. Lind et al. able to address individual CVD risk factors and are
in his longitudinal cohort study on 719 patients with being evaluated, including endo-cannabinoid re-
oral anticoagulant revealed the association of CVD ceptor antagonists, peroxisome proliferator inhibi-
62
with higher level of D-dimer. Fruchter et al. , tor are regulating the activity of glucagon-like pep-
4
based on data from clinical and laboratory, pro- tide-1 .
posed D-dimer as prominent prognostic marker of Acknowledgments: Authors thank Dr. A. Vijaya
short and long term survivors subjected to acute Anand, Head of the department of Human Genet-
exacerbation. He also noticed the changes in the ics and Molecular Biology, Bharathiar Univeristy,
mean D-dimer level in non-survivors (3.18 mg/L
Coimbatore for his valuable suggestion and correc-
and survivors (1.45 mg/L).
tion.
Interleukin
Conflict of interest: None
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