Received: 17 November 2018 | Revised: 22 January 2019 | Accepted: 24 January 2019

DOI: 10.1002/jcp.28350

REVIEW ARTICLE

A review on coronary artery disease, its risk factors, and

therapeutics

Arup Kr. Malakar1* | Debashree Choudhury1* | Binata Halder1* | Prosenjit Paul1* |

Arif Uddin 2
| Supriyo Chakraborty 1

1
Department of Biotechnology, Assam
University, Silchar, Assam, India Abstract
2
Department of Zoology, Moinul Hoque Coronary artery disease (CAD) is one of the major cardiovascular diseases affecting
Choudhury Memorial Science College,
the global human population. This disease has been proved to be the major cause of
Hailakandi, Assam, India
death in both the developed and developing countries. Lifestyle, environmental
Correspondence
factors, and genetic factors pose as risk factors for the development of cardiovascular
Supriyo Chakraborty, Department of
Biotechnology Assam University, Silchar disease. The prevalence of risk factors among healthy individuals elucidates the
788011, Assam, India.
probable occurrence of CAD in near future. Genome‐wide association studies have
Email: supriyoch_2008@rediffmail.com
suggested the association of chromosome 9p21.3 in the premature onset of CAD. The
risk factors of CAD include diabetes mellitus, hypertension, smoking, hyperlipidemia,
obesity, homocystinuria, and psychosocial stress. The eradication and management of
CAD has been established through extensive studies and trials. Antiplatelet agents,
nitrates, β‐blockers, calcium antagonists, and ranolazine are some of the few
therapeutic agents used for the relief of symptomatic angina associated with CAD.

KEYWORDS
cardiovascular disease, coronary artery disease, low‐density lipoproteins

1 | INTRODUCTION
Coronary artery disease (CAD) is a cardiovascular disease which has
been found to be the leading cause of death in both developed and
developing countries (Naghavi et al., 2015). CAD is an atherosclerotic
disease which is inflammatory in nature (Ross, 1999), manifested by
stable angina, unstable angina, myocardial infarction (MI), or sudden
cardiac death (Álvarez‐Álvarez, Zanetti, Carreras‐Torres, Moral, &
Athanasiadis, 2017). From genome‐wide association studies (GWAS),
several genetic variants have been found to be robustly associated
with CAD (Lieb & Vasan, 2013). A recent study on the genetic
differences in CAD risk among populations worldwide was reported
to be due to demographic processes (Corona, Dudley, & Butte, 2010).
Genetic and environmental factors have been found to interact with
one another to determine the clinical phenotype of cardiovascular
diseases (Girelli, Martinelli, Peyvandi, & Olivieri, 2009). Moreover,
*Malakar, Choudhury, Halder, and Paul have contributed equally.
J Cell Physiol. 2019;1–12.
lifestyle has been found to play an important role in the development
of such cardiovascular diseases (Yusuf et al., 2004).
Approximately 6 million deaths occurred in the American
populations in the year 2005 due to CAD (Lloyd‐Jones et al.,
2009). In the year 2007, it has been reported that approximately one
in 30 patients with CAD experiences death each year (Steg et al.,
2007). According to the World Health Organization report, sub-
mitted in the year 2009, 17.3 million deaths occurred due to
cardiovascular diseases (Álvarez‐Álvarez et al., 2017). CAD was
found to be one of the major causes of disability and death in the
Indian population (Gupta, Guptha, Sharma, Gupta, & Deedwania,
2012) and its contribution to mortality has been found to increase as
the number of deaths due to CAD increased from the year 1985 and
was expected to be doubled by the year 2015 (Misra et al., 2012).
Preventive and therapeutic measures have substantially
improved the prognosis of patients suffering from CAD or other
cardiovascular diseases over the past few decades (Antiplatelet
Trialists’ Collaboration, 1994; Scandinavian Simvastatin Survival
Study Group, 1994). However, the risk of such diseases seems to
wileyonlinelibrary.com/journal/jcp © 2019 Wiley Periodicals, Inc. | 1
2 |
remain high and their progression could be halted only in a few
patients by using treatments involving aspirin, statins, and β‐blockers
(Lloyd‐Jones et al., 2009).
The information on the first emergence of CAD cannot be dated
precisely (Lichtlen, 2002). However, in the 17th century, the clinical
description of angina was described by Heberden (Silverman, 1987).
Friedrich Hoffmann, a chief professor of a cardiologist in the
University of Halle, for the first time, described the origins of
coronary heart diseases by stating that the origin of such disease lies
in the passage of reduced blood within the coronary arteries
(Lichtlen, 2002). Almost a century later, pathologists focused on
coronary arteries and thrombotic occlusions (Nabel & Braunwald,
2012). By the end of the 19th century, physiologists observed that
occlusions of a coronary artery in a dog resulted in slight vibrations
of the ventricles and it became rapidly fatal (McWilliam, 1889). By
1879, pathologists concluded that coronary thrombosis was the
cause of MI (Hektoen, 1892). In 1919, electrocardiography was used
for the diagnosis of CAD (Herrick, 1919).
1.1 | Prevalence of CAD
The prevalence of CAD, also known as coronary heart disease
(CHD), has been observed to vary greatly according to the
geographical locations, ethnicity, and gender (Go et al., 2014).
Epidemiological studies on such cardiovascular diseases have
provided information which could guide the strategies of preven-
tion and eradication of these diseases both at the individual and
population levels (Wong, 2014). Even before the field of
cardiovascular epidemiology existed, in Minnesota (United States)
the first prospective studies of CAD prevalence in population was
conducted in 1946 (Keys et al., 1963). In the seven countries study,
the relationships between lifestyle, diet, CAD, and stroke were
elucidated (Keys, 1980). This study also indicated that the rates of
heart attack and stroke were directly related to the levels of total
cholesterol and this remained constant across different countries
and cultures (Epstein, 1996).
The Monitoring Trends and Determinants in Cardiovascular
Diseases (MONICA) project was one of the largest and important
studies involved in determining the international incidence of CHD
and cardiovascular diseases in various populations over a period of
10 years (World Health Organization, 1988). This study began in
1979 and focused on the evaluation of CAD trends in a total
population of approximately 15 million men and women in the age
group of 25–64 years. This study reported the survival and coronary
event rates (Tunstall‐Pedoe et al., 1999).
Another important contribution in the field of epidemiology of
CAD was the INTERHEART study that helped in understanding the
prevalence of CAD in different populations. This study was intended
to explore the wide array of risk factors associated with acute MI
prevailing in different ethnic groups across different geographical
locations, which included 52 countries throughout Africa, Asia,
Australia, Europe, the Middle East, and North and South America
(Yusuf et al., 2004).
MALAKAR ET AL.
In understanding the epidemiology of CAD, a “natural
experiment” named as the Nippon–Honolulu–San Francisco
(Ni‐Hon‐San) was conducted in the1960s, which included cross‐
sectional evaluation of CAD among different migrant Japanese men
aged 45–69 years, living in Hawaii and California and native Japanese
men in the same age group, living in Japan (Worth, Kato, Rhoads,
Kagan, & Syme, 1975). The findings of this study proved that changes
in the lifestyle were associated with acculturation that could
potentially explain the changes in cardiovascular disease risks (Worth
et al., 1975). Higher cholesterol levels and higher CAD mortality
rates were evident in Japanese migrants residing in America than the
native Japanese men residing in Japan (Sekikawa et al., 2003; Worth
et al., 1975). In 2010, the prevalence of CAD in the United States was
observed to be the greatest among the people in the age group of
more than 65 years (19.8%), which was followed by people in the
age group of 45–64 years (7.1%), and then in the age group of
18–44 years (1.2%; Centers for Disease Control and Prevention
[CDC], 2011). In 2012, CAD caused 46% of deaths attributed
to cardiovascular diseases in the United Kingdom (Bhatnagar,
Wickramasinghe, Williams, Rayner, & Townsend, 2015).
In 2016, American Heart Association released an updated report
of Heart Disease and Stroke Statistics, which reported that in the
United States, 15.5 million people above 20 years of age suffer from
CHD (Mozaffarian et al., 2016). This prevalence was found to be
increasing with age in both men and women (Mozaffarian et al.,
2016). In India, CAD has, of late, gained importance as a major
disease (Krishnan et al., 2016). During the period from 1984 to 1987,
a study conducted in Delhi reported 9.7% prevalence of CAD in
urban and 2.7% prevalence in rural populations and the sample
comprised of men and women in the age group of 24–64 years
(Chadha, Radhakrishnan, Ramachandran, Kaul, & Gopinath, 1990).
2 | ETIOLOGY
The CAD is a cardiovascular disorder occurring due to athero-
sclerosis or atherosclerotic occlusions of the coronary arteries
(Mendis, Puska, Norrving, & Organization, 2011; Ross, 1999).
When the endothelial function of the arterial wall disrupts,
atherosclerosis starts due to the accumulation of lipoprotein
droplets in the intima of the coronary vessels (Badimon, Padró, &
Vilahur, 2012). In the bloodstream, water‐insoluble lipids circulate
by attaching themselves to water‐soluble lipoproteins called
apolipoproteins. Low‐density lipoproteins (LDL) in high concentra-
tion possess the ability to permeate the disrupted endothelium
and undergo oxidation (Ibanez, Vilahur, & Badimon, 2007). This
oxidized or modified LDL then attract leukocytes into the intima of
the coronary vessels, which can be scavenged by macrophages,
leading to the formation of foamy cells. These foamy‐texture cells
replicate and form lesions, which are named as a fatty streak. This
is the earliest form of lesions visualized in atherosclerosis. The
formation of such lesions triggers signals which attract smooth
muscle cells (SMCs) to the site of the fatty streak. The SMCs then
MALAKAR ET AL.
F I G U R E 1 Pathophysiology of coronary
artery disease depicting the formation of
atherosclerotic plaque in the arteries that
leads to obstructed blood flow through the
arteries [Color figure can be viewed at
wileyonlinelibrary.com]
start proliferation and production of extracellular matrix, mainly
collagen and proteoglycans. The atherosclerotic plaque starts
developing and accumulates a large volume of extracellular matrix
produced by the SMCs, leading to the progression of the lesion to
fibrous plaque (Figure 1). The fibrous plaque encroaches on the
lumen of the coronary vessel and small blood vessels are formed
which can subsequently calcify the plaques. The final lesion formed
is an advanced and complicated lesion comprising of a fibrous cap
with an overlying lipid‐rich core containing necrotic material, that
may be highly thrombogenic (Ross, 1999).
The proteoglycans produced by the SMCs can bind to lipopro-
teins and prolong their existence in the intima, thereby rendering
them susceptible to oxidative modifications and nonenzymatic
conjugation with sugars, also called glycation (Williams & Tabas,
1998). The modified lipoproteins, namely, oxidized phospholipids and
advanced glycation end products can propagate inflammatory
responses (Berliner, Subbanagounder, Leitinger, Watson, & Vora,
2001; Tabas, 1999).
| 3
Matrix metalloproteinases (MMPs) are secreted by the endothe-
lial cells in response to oxidation, hemodynamic, inflammatory, and
autoimmune signals (Libby & Lee, 2000). These MMPs, along with a
balance of their endogenous tissue inhibitors, modulate various
functions of the vascular cells, such as activation, migration,
proliferation, cell death, geometric remodeling, new vessel formation,
destruction of the extracellular matrix of arteries, and myocardium
and healing (Libby & Lee, 2000). Cell death or apoptosis occurs
commonly in the atherosclerotic lesions, which eventually leads to
the deposition of tissue factor in particulate form (Bogdanov
et al., 2003).
As a result of the formation of the atherosclerotic plaque in the
coronary artery, obstruction of blood flow occurs which leads to a
mismatch between myocardial oxygen demand and supply (Cassar,
Holmes, Rihal, & Gersh, 2009). This obstruction manifests the
symptoms of CAD such as substernal discomfort, heaviness, a
pressure‐like feeling, which may radiate to the jaw, shoulder, back,
or arm. These symptoms typically last for several minutes and are
4 |
usually brought on by a heavy meal, emotional stress, exertion, or
cold. Within minutes, these symptoms could be relieved by rest or
nitroglycerin (Cassar et al., 2009).
3 | GEN ETIC B ASIS OF C AD
Family clustering of CAD was reported in the 1950s and 1960s (Rose,
1964; Thomas & Cohen, 1955). The heritability of CAD risk has been
reported to increase with the increase in the number of affected
relatives and onset in a young age (Nora, Lortscher, Spangler, Nora, &
Kimberling, 1980). Mendelian disorders have been found to be
associated with CAD, which includes familial hypercholesterolemia
(Antonarakis & Beckmann, 2006). Hypercholesterolemia is a single
gene disorder caused by mutations in the LDL receptor genes (LDLR),
in the lipid‐binding domain of apolipoprotein B100 (APOB) and
proprotein convertase substilisin/kexin type 9 gene proprotein
convertase substilisin/kexin type 9 gene (PCSK9) (Antonarakis &
Beckmann, 2006). Understanding the molecular basis of such disorders
led to the discovery of pathways of LDL cholesterol metabolism which
is associated with pathogenesis of CAD (Kullo & Ding, 2007).
Variations in the genes associated with such disorders could be
helpful in determining the disease susceptibility of the general
population (Kullo & Ding, 2007).
Genome‐wide association analysis of CAD suggested that
chromosome 9p21.3 was associated with CAD (Samani et al.,
2007). In such studies, it was reported that 396 single‐nucleotide
polymorphisms (SNPs) were associated with CAD, of which 30 SNPs
were clustered in nine chromosomal regions (Samani et al., 2007).
The 9p21.3 locus was reported to contain coding sequences of two
cyclin‐dependent kinases, namely, CDKN2A and CDKN2B, which
were associated in the regulation of the cell cycle and might have a
role in transforming growth factor β (TGF‐β)‐induced growth
inhibition, which is involved in the pathogenesis of CAD (Kalinina
et al., 2004; Lowe & Sherr, 2003). pRb pathway is inhibited by
p16INK4a and p15INK4b which are coded by CDKN2A and
CDKN2B, respectively, whereas p14ARF coded by CDKN2A inhibits
both the p53 and pRb pathways, thereby regulates cell division.
p16INK4a and p15INK4b specifically bind to CDK inhibitors 6 and 4,
causes cell‐cycle arrest in G1 phase. The knock‐out of CDKN2A or
CDKN2B in mice is kenned to cause tumors within months (Bellary,
Murthy, Vala, Hanumanth, & Quraishi, 2016; Krimpenfort et al.,
2007). Another gene named methylthioadenosine phosphorylase
(MTAP) is also found in 9p21.3 locus, which is observed in many
different human tumors (Kadariya et al., 2009; Kim et al., 2012).
Tissues that are affected by atherosclerosis contains a noncoding,
antisense RNA of unknown function, named antisense noncoding RNA
in the INK4 locus (ANRIL), also known as CDKN2B‐AS (Pasmant et al.,
2007). ANRIL plays a critical part in the regulation of gene expression
(Broadbent et al., 2007). Many research reports denuded the variants
associated with CAD arbitrate CAD risk by altering expression of
ANRIL, CDKN2A, CDKN2B via multiple cis‐regulatory elements
(Cunnington, Koref, Mayosi, Burn, & Keavney, 2010; Harismendy
MALAKAR ET AL.
et al., 2011). A dense assembly of gene expression enhancers and
CAD risk SNPs were observed in the risk region, many of which showed
their effect in disrupting the binding site for the transcription factors
(Harismendy et al., 2011; Pilbrow et al., 2012). The ultimate effect of
many of these activated regulators of the cell‐cycle progression
pathway on the advancement of CAD is still unknown.
CAD is a complex disease caused by genetic and environmental
factors and the interactions between these factors (Wang, 2005b).
Family history is one of the significant risk factors for the
development of this disease (Schildkraut, Myers, Cupples, Kiely, &
Kannel, 1989). Case–control association studies have been carried
out to identify the susceptible genes responsible for CAD (Shen,
Archacki, & Wang, 2004; Wang, 2005a, 2005b; Wang & Chen, 2000).
The genes associated with this disease can be classified into three
categories: disease‐causing genes, susceptibility genes, and disease‐
linked genes.
Disease‐causing genes are the genes directly responsible for the
development of CAD and have high predictive values (Wang, 2005b).
Mutations in these genes lead to the pathogenesis of CAD and can be
used for genetic testing. Disease‐causing genes have been identified
for Tangier disease and familial hypercholesterolemia, which pose as
risk factors for premature onset of CAD. Familial hypercholester-
olemia is caused by mutations in the LDLR gene (Hobbs, Russell,
Brown, & Goldstein, 1990), ApoB100 gene (Lund‐Katz, Laplaud,
Phillips, & Chapman, 1998), PCSK9 (Abifadel et al., 2003; Ouguerram
et al., 2004), cholesterol 7‐α‐hydroxylase gene (CYP7A1; Pullinger
et al., 2002), and ARH gene (Garcia et al., 2001). The genes mutated
in Tangier disease have been identified as ABCA1 gene encoding the
ATP‐binding cassette transporter family, which is involved in the
efflux of lipids from the peripheral cells to Apo A1 forming nascent
high‐density lipoprotein (HDL) particles (Bodzioch et al., 1999;
Brooks‐Wilson et al., 1999).
Through numerous case–control studies, SNPs or genetic variants
of many candidate genes have been identified and found to be
associated with increased or decreased risk for CAD (Shen et al.,
2004; Wang & Chen, 2000). Some of the susceptibility genes
identified by positional cloning and GWAS are USF1 and lymphotoxin
α (Wang, 2005b). USF1 is a gene encoding a transcription factor that
regulates the genes involved in glucose and lipid metabolism.
Mutations in USF1 cause familial combined hyperlipidemia (FCHL),
which poses as a risk factor for the premature onset of CAD and MI
(Pajukanta et al., 2004). Lymphotoxin α is another susceptibility gene
mediating immune responses and inflammation and has been
suspected to be associated with MI (Koch et al., 2001; Ozaki et al.,
2002; Yamada et al., 2004).
Disease‐linked genes are those whose expression is linked to
CAD and MI and have been identified by genomic and proteomic
approaches. These genes serve as biomarkers for this disease (Wang,
2005b). Expression of 49 genes has been linked to CAD by
microarray analysis and includes intercellular adhesion molecule‐2,
PIM2, ECGF1, fusin, B‐cell activator (BL34, GOS8), Rho GTPase
activating protein‐4, retinoic acid receptor, and β2 arrestin (Archacki
et al., 2003). Proteomic study of CAD included the separation of
MALAKAR ET AL.
proteins from CAD and non‐CAD coronary arteries by two‐
dimensional gel electrophoresis where protein spots with different
expression levels, obtained from two tissues, were excised and
analyzed by mass spectrometry (You et al., 2003). The results of this
study reported an association between excessive iron storage and a
high risk of CAD where expression of the ferritin light chain was
found to be significantly elevated in the diseased arteries by about
twofold, thus linking the ferritin light chain gene to CAD (You
et al., 2003).
In countries such as the United Kingdom, the United States,
and Europe, GWAS and consortia‐based studies have reported
the involvement of 45 genes in the pathogenesis of CAD (Reilly
et al., 2011). Some of these genes are SORT1, MIA3, WDR12,
PCSK9, CDKN2A, CDKN2B, MRAS, ANRIL, PHACTRI1, PTPN11,
ATXN2, CXCL12, SL5A3, SH2BS, LDLR, KCNE2, and MRPS6
(Reilly et al., 2011). In South Asians, certain novel genes for CAD
have been identified by C4D Genetics Consortium, which
includes LIPA at chromosome 10q23, PDGFD on chromosome
11q22, ADAMTS7‐MORF4L1 on chromosome 15q25, a gene‐rich
locus on chromosome 7q22 and KIAA1462 on chromosome
10p11 (Consortium CADG, 2011).
Linkage analysis and gene discovery studies were carried out to
understand the phenomenon of familial clustering of CAD with
collections of large pedigrees consisting of multiple members in
multiple generations (Dai, Wiernek, Evans, & Runge, 2016). From
such studies and analyses, three potential causal genes have been
found to be associated with Mendelian autosomal dominant (AD)
CAD and MI (Dai et al., 2016). MEF2A acts as a transcription factor
which belongs to the monocyte enhancer factor (MEF) family.
During embryogenesis, this factor is expressed in blood vessels and
acts as an early marker of vasculogenesis (Dai et al., 2016). This
factor shows interactions with a number of molecules which are
F I G U R E 2 Various risk factors
associated with coronary artery disease
[Color figure can be viewed at
wileyonlinelibrary.com]
| 5
known to be involved in the pathogenesis of cardiovascular
diseases. In individuals with premature onset of CAD, missense
mutation in this gene led to loss‐of‐function of MEF2A (Liu et al.,
2005; Zhu, Fejerman, Luke, Adeyemo, & Cooper, 2005). CYP27A1 is
a cytochrome (CY) P450 oxidase encoding gene that has been
identified as a causal gene of CAD. Mutation in this gene was
reported to be associated with CAD phenotype (Dai et al., 2016).
However, the disease‐causing variants appear rarely in populations.
ST6GALNAC5 gene encodes a Golgi type II transmembrane
glycosyltransferase protein which catalyzes the transfer of sialic
acid to cell surface proteins to modulate cell–cell interactions. It is
the newest addition to the causal genes responsible for CAD (Dai
et al., 2016). Mutational studies of this gene have revealed that it is
involved atherosclerosis (Pritchard & Rosenberg, 1999).
3.1 | Risk factors associated with CAD
The risk factors associated with the development of CAD have been
established by extensive epidemiological research and these are
smoking (US Department of Health and Human Services, 1990),
diabetes (Stamler, Vaccaro, Neaton, Wentworth, & Group MRFITR.,
1993), hyperlipidemia (Verschuren et al., 1995), and hypertension
(MacMahon et al., 1990; Figure 2).
About 30–40% of annual deaths have been estimated to be
related to CAD, which are attributable to smoking (US Department of
Health and Human Services, 1990). Case–control studies and cohort
studies involving 20 million people clearly made it clear that a higher
incidence of death due to CAD has been revealed in smokers than
in nonsmokers. Smokers have been reported to have 70% more
CAD mortality than nonsmokers. The adverse effects of cigarette
smoking demonstrated dose–response relationship with cardiovas-
cular diseases which suggest that the risk of developing CAD
6 |
increases with increased duration of smoking, number of cigarettes
smoked and increased indepth of smoke inhalation. Smoking has
been reported to contribute to CAD morbidity and mortality either
directly or indirectly have an influence on the atherosclerotic lesion.
Smoking also promotes coronary occlusion as it produces endothelial
denudation and platelet adhesion to subintimal layers, thereby
increasing lipid infiltration and platelet‐derived growth factor
(PDGF)‐mediated proliferation of SMCs (US Department of Health
and Human Services, 1990).
Diabetes, particularly diabetes mellitus or type 2 diabetes poses
as a risk factor of CAD (Haffner, 1999; Kannel & McGee, 1979). This
risk of suffering from CAD has been observed to be higher in patients
with diabetes than in non‐diabetes (Wagenknecht, D'agostino,
Haffner, Savage, & Rewers, 1998). Diabetes has been observed to
be often associated with hyperlipidemia, which is characterized by
increased levels of triglycerides and decreased levels of HDL
cholesterol (Haffner, 1999; Wilson, Kannel, & Anderson, 1984).
Low levels of HDL cholesterol, high levels of very low‐density
lipoprotein (VLDL) cholesterol and high levels of total VLDL
triglycerides have been reported as risk factors for CAD in patients
with type 2 diabetes (Laakso, Lehto, Penttilä, & Pyörälä, 1993). Many
studies were conducted to demonstrate the use of drugs to decrease
the incidence of CAD in diabetic patients (Haffner, 1999).
A strong association between hypertension and CAD has been
reported in the PROCAM study, indicating the prevalence of
hypertension in patients of MI in a follow‐up of 4 years (Assmann &
Schulte, 1988). There exists pathophysiologic association between
hypertension and CAD as atherosclerosis could be exacerbated by
arterial hypertension (Chobanian & Alexander, 1996). Due to the
deposition of lipids and formation of atherosclerotic plaques in the
arteries, transmural pressure in the arteries increases. It exerts an
increasing mechanical stress and endothelial permeability, thereby
contributing to a decrease of coronary response (Strauer, 1992).
Hypertension has also been frequently associated with metabolic
disorders like insulin resistance or hyperinsulinemia and dyslipide-
mia, which are also known to be the risk factors of CAD (DeFronzo &
Ferrannini, 1991).
Obesity, also defined as the excess accumulation of fat in the
adipose tissues, has been reported to be a common cause of
cardiovascular deaths in the developed countries (Matsuzawa,
Nakamura, Shimomura, & Kotani, 1995). Excess body fat in the
abdominal visceral can lead to atherosclerotic disease (Matsuzawa
et al., 1995). Dysregulation of the adipocyte‐derived endocrine
factors occurring in overnutrition has been assumed to participate in
the development of atherosclerosis (Kumada et al., 2003).
Homocystinuria is an inherited recessive disorder or error of
methionine metabolism (McKusick, 1972). In such a disorder, high
levels of circulating homocysteine and urinary homocysteine have
been reported (Mudd et al., 1985). Individuals with such disorders
have been found to be prone to premature onset of cardiovascular
diseases (Mudd et al., 1985). Homocysteine has been implicated to be
involved in the development of atherosclerosis (McCully, 1969).
Evidence suggests that the coagulation system might be affected by
MALAKAR ET AL.
homocysteine and the endothelium was reported to be resistant to
thrombosis (Malinow, 1994).
Hyperuricemia is generally defined as the excess of serum urate
concentration present in the body (Becker, 1993). Serum uric acid is
the product of purine metabolism (Becker, 1993; Sinha, Singh, & Ray,
2009), which when present at a concentration more than 6.8 mg/dl,
causes hyperuricemia (Becker, 1993). Studies have indicated a
relationship between hyperuricemia and risk of CAD (Chuang, Chen,
Yeh, Wu, & Pan, 2012; Kavousi et al., 2012; Storhaug et al., 2013;
Zalawadiya et al., 2015). Extensive research is still underway to
determine the association of hyperuricemia with CAD risk and stroke
(Dutta, Henley, Pilling, Wallace, & Melzer, 2013; Li, Hou, Zhang, Hu, &
Tang, 2014; Savarese et al., 2013; Skak‐Nielsen et al., 2013; Zhao,
Huang, Song, & Song, 2013). Many plausible mechanisms related to this
association have been proposed that state the involvement of uric acid
in the stimulation of vascular smooth cell proliferation, reduction in
vascular nitric oxide production and activity and also may be linked to
insulin resistance (Waring, McKnight, Webb, & Maxwell, 2007).
However, such proposed mechanisms remain controversial to prove
the role of serum uric acid to CAD risk. Despite this, serum uric acid
has been found to be positively associated with arterial intima‐media
thickness, which is a precursor of atherosclerosis (Dawson, Quinn, &
Walters, 2007; Montalcini et al., 2007; Waring et al., 2007). Stress has
been recognized as an important and potentially modifiable risk factor
for cardiovascular diseases (Steptoe & Kivimäki, 2012). Various
physiological changes produced by stress may be relevant to
cardiovascular diseases (Steptoe & Kivimäki, 2012). Such responses
include elevated blood pressure, reduced insulin sensitivity, elevated
hemostasis, and endothelial dysfunction (Brotman, Golden, &
Wittstein, 2007).
Psychosocial stress involving job strain has been found to be a
risk factor of CAD (Steptoe & Kivimäki, 2012). Job strain has been
defined as the combination of high job demands and low control at
work (Kivimäki, Theorell, Westerlund, Vahtera, & Alfredsson, 2008).
In a case–control study of INTERHEART, job strain was reported to
be associated with a higher risk of MI in men than in women
(Rosengren et al., 2004). It has also been suggested by some studies
that the effect of job strain in younger employees was higher than in
older employees (Kivimäki et al., 2008).
4 | THERAPEUTICS
Recent advances in the field of therapeutics have suggested the
possibilities of novel therapeutic approaches in the management and
treatment of CAD (Carmeliet, 2000b).
4.1 | Treatment using angioplasty and stent
placement
Coronary angioplasty also is known as percutaneous coronary
intervention, is a procedure used during a heart attack to quickly
open a blocked artery and reduce the amount of damage to the heart
MALAKAR ET AL.
(Parisi, Folland, & Hartigan, 1992). It involves temporarily inserting
and inflating a tiny balloon where artery is clogged to enlarge the
artery. The angioplasty reduces the symptoms of blocked arteries,
such as chest pain and breath shortness.
To decrease the chance of artery contraction over again, a small
wire mesh tube (stent) is placed permanently to keep the artery
open. Two different types of stents are used at large: drug‐eluting
stents and bare metal stents to keep the artery open (Serruys,
Kutryk, & Ong, 2006).
4.2 | Treatment using recombinant fibroblast
growth factor 2 (FGF2)
FGF2, being a pluripotent growth factor, has the capability of
stimulating growth and migration of cell types (Szebenyi & Fallon,
1998). This factor has been found to promote vascular tree branching
(Carmeliet, 2000a). Through tyrosine kinase receptors (Klint &
Claesson‐Welsh, 1999) and syndecan 4 heparin sulfate core protein
(Simons et al., 2002), the fibroblast growth factor triggers signals and
increases the expression of such receptors in the ischemic
myocardium, thereby promoting responsiveness to FGF2 stimulation
(Simons et al., 2002). Preclinical studies have demonstrated the
therapeutic efficacy of FGF2 in chronic ischemia model by
augmentation of coronary flow (Lazarous et al., 1996; Unger et al.,
1994) and ventricular function (Lopez et al., 1997). Clinical efficacy of
FGF2 was demonstrated by a small randomized trial of sustained‐
release of FGF2 implanted in the myocardium during surgery (Laham
et al., 1999). Thus, research supports the efficacy of FGF2 as an
angiogenic agent used in the treatment of atherosclerosis (Simons
et al., 2002). It has been reported that a single intracoronary infusion
of recombinant FGF2 (rFGF2) in advanced CAD patients proved to
be well tolerated and safe (Simons et al., 2002).
4.3 | Treatment using antiplatelet agents
Antiplatelet agents or antiplatelet drugs have been reported to be
used in CAD treatment and these include aspirin, sulfinpyrazone,
and nonsteroidal anti‐inflammatory agents (Schrader & Berk,
1990). These drugs could alter platelet function by inhibiting the
activity of an enzyme necessary for the production of prostaglan-
dins, known as cycloxygenase. Regular aspirin ingestion by MI
patients could reduce the occurrence of cardiovascular complica-
tions although daily dose of aspirin was suggested not to be more
than 325 mg (Schrader & Berk, 1990). However, the use of such
drugs was not recommended for patients with high risk of bleeding
(Schrader & Berk, 1990).
Platelets secrete TXA‐2 protein, which leads to platelet recruit-
ment and activation (Clappers, Brouwer, & Verheugt, 2007). Within
the activated platelets, TXA‐2 is formed from arachidonic acid
metabolism which is catalyzed by the enzyme cyclo‐oxygenase 1
(COX‐1). This COX‐1 enzyme could be inactivated by aspirin, thereby
completely abolishing TXA‐2 formation and reduces platelet function.
This is the main mechanism of protection against thrombotic events
| 7
(Clappers et al., 2007). It has already been established that aspirin
inhibits platelets in the portal circulation, before its entry in the
systemic circulation. The standard dosage of aspirin ranges from 75
to 150 mg per day for long‐term use, however, in the acute phase, a
loading dose of 150–325 mg has been recommended (Antiplatelet
Trialists’ Collaboration, 2002). A trial was carried out to compare the
antiplatelet treatment in patients with stable angina pectoris
(Juul‐Moller et al., 1992). The trial indicated a clear reduction in
the primary end point of fatal and nonfatal MI or sudden cardiac
death. This proves that patients with stable coronary disease could
be treated with aspirin (Juul‐Moller et al., 1992).
Another antiplatelet drug, namely thienopyridines are biologically
inactive prodrugs which are metabolized to the active form by
CYP450 system in the liver (Clappers et al., 2007). These drugs could
irreversibly block the P2Y12 receptor present on the platelet
surface. When ADP binds to this P2Y12 receptor, a cascade of
events is initiated which leads to activation of glycoprotein IIb/IIIa
receptor. The glycoprotein IIb/IIIa receptors are involved in strong
and irreversible platelet aggregation (Clappers et al., 2007). In clinical
practice, the first thienopyridine used was ticlopidine, which was
later replaced by clopidogrel due to hematological and dermatolo-
gical side effects. Prasugrel, another type of thienopyridine, is
currently under investigation in a Phase III trial in patients who
have undergone percutaneous coronary intervention (Clappers
et al., 2007).
Glycoprotein IIb/IIIa receptors are the actual receptors for
fibrinogen, which are activated on platelet activation (Clappers
et al., 2007). Whenever the platelets are activated despite the action
of other antiplatelet drugs, because of insensitivity to such drugs,
glycoprotein IIb/IIIa blocks may be used (Clappers et al., 2007). These
blockers were developed to irreversibly bind and inactivate these
receptors. Examples of such blockers include abciximab, tirofiban,
and eptifibatide (Clappers et al., 2007).
4.4 | Treatment using other therapeutic agents
β‐Blockers administration to CAD patients was found to reduce heart
rate and metabolic requirements to the myocardium, thereby
preventing ischemia (Jonas et al., 1996). These therapeutic agents
could be used for angina, hypertension, rhythm management, and
asthma and can improve symptomatic angina by reducing myocardial
oxygen demand and elevating myocardial oxygen supply (Quyyumi,
Crake, Wright, Mockus, & Fox, 1987). It has been also noted that
patients receiving β‐blockers showed better prognosis, indicating the
benefits of such drugs (Jonas et al., 1996). Thus, β‐blockers therapy
appeared to improve long‐term survival in older patients with CAD
(Jonas et al., 1996).
Nitrates in the form of sublingual nitroglycerin or nitroglycerin
sprays have been used for immediate relief of angina by relieving the
symptoms alone by increasing the myocardial oxygen supply and
decreasing the myocardial oxygen demand (Tadamura et al., 2003).
These therapeutic agents are recommended as additives if β‐blockers
alone are inefficient (Akhras & Jackson, 1991).
8 |
Calcium antagonists are drugs used for coronary vasospasm
to gain relief from symptoms only, in addition to β‐blockers
therapy (Chahine et al., 1993; Savonitto et al., 1996). These
therapeutic agents relieve symptoms by decreasing the myocar-
dial oxygen demand and increasing myocardial oxygen supply
(Quyyumi et al., 1987).
Patients with chronic angina or chest pain were treated with
ranolazine for symptomatic relief as this drug has the ability to alter
the transcellular sodium current, thereby decreasing the intracellular
calcium, which results in lesser ischemia (Rousseau, Pouleur, Cocco, &
Wolff, 2005). It has been reported that these drugs can reduce high
blood glucose levels (Morrow et al., 2009) and also decrease the death
rate (Wilson et al., 2009).
5 | CONC LU SION
CAD also is known as atherosclerosis or CHD has been found
to be the major cause of mortality and morbidity in human.
Extensive studies on the epidemiology of CAD have suggested the
prevalence of CAD in almost all parts of the world. In the
developing countries, these cardiovascular diseases are becoming
pandemic. Several consortia, case–control studies, epidemiological
studies, and genome‐wide association analysis have been carried
out in understanding various aspects of this disease. The genetic
basis of premature onset of CAD has insufficient information on
which further work can be carried out. Most causal genes and loci
of CAD appear rarely in populations and the reason for such
uneven distribution of genes among populations has not yet been
deduced. Many facts and figures have been published that
describe the current status of the prevalence of such cardiovas-
cular diseases. Lack of awareness makes it more adverse and
difficult to manage. Understanding the risk factors associated,
adopting healthy lifestyle and preventive strategies and early
diagnosis could be very crucial for the management and eradica-
tion of such cardiovascular diseases. Further research could be
carried out to understand the development of such cardiovascular
diseases among populations to elucidate the preventive and
therapeutic approaches for proper management and eradication
of CAD.
A C K N O W L E D GM E N T
The authors thank Assam University, Silchar, Assam, India, for
providing the necessary facilities in carrying out this review work.
CO NFLICT OF I NTERE STS
The authors declare that there are no conflict of interests.
OR CID
Supriyo Chakraborty http://orcid.org/0000-0002-5996-2760
MALAKAR ET AL.
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How to cite this article: Malakar AK, Choudhury D, Halder B,
Paul P, Uddin A, Chakraborty S. A review on coronary artery
disease, its risk factors, and therapeutics. J Cell Physiol.
2019;1–12. https://doi.org/10.1002/jcp.28350