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Current Pharmaceutical Design, 2015, 21, 4479-4497 4479
Recent Advancement in the Treatment of Cardiovascular Diseases: Conventional
Therapy to Nanotechnology
Sudhanshu S. Beheraa, Krishna Pramanika and Manasa K. Nayaka,b*
aDepartment of Biotechnology and Medical Engineering, National Institute of Technology, Rourkela 769008,
India; bDepartment of Internal Medicine, University of Iowa, Iowa city, 52242, USA
Abstract: Cardiovascular disease (CVD), accounting around 30% of deaths worldwide, collectively comprised of
disorders affecting the heart and blood vessels as well as their associated adverse conditions. Despite outstanding
progress in the area of the treatments of CVDs, significant challenges remain in designing of efficient delivery sys-
tems for myocardial therapy. Moreover, current therapy for CVDs is limited due to various clinical complications
such as systemic toxicity, stent thrombosis, etc. Molecular and nanotechnology approaches provide the tools to ex-
plore such frontiers of biomedical science at the cellular level and thus offer unique features for potential applica-
tion in the field of cardiac therapy. In this review, recent advances in CVD related risk factors, chronic inflamma-
tion, and their therapeutic modalities such as stem cell therapy, gene delivery, tissue factor (TF) inhibitors, miR-
NAs, leukotriene modifiers, thrombolytic agents etc., in modern molecular aspects are discussed. Moreover,
nanoparticle based drug delivery, nanocarriers as molecular imaging, and the various challenges of myocardial tissue engineering aspects
have been summarized. All these aspects may provide additional therapeutic substitutes in clinical trials for the registration of new drugs.
Keywords: Cardiovascular disease (CVD), inflammation, potential therapeutics, nanotechnology.
1. INTRODUCTION
Cardiovascular diseases (CVDs) are a group of disorders of the
heart, the associated blood vessels (BVs) (such as arteries, veins,
and capillaries) or both [1]. These comprise of coronary heart dis-
eases, cerebrovasular diseases, peripheral arterial diseases, rh euma-
toid heart diseases, congenital heart diseases, deep vein thrombosis
(DVT) and pulmonary embolism (PE) [2]. Moreover, heart attacks
and strokes are usually acute events, caused by a blockage that
prevents blood from flowing to the heart and brain, respectively
[3,4]. The major cause for this is a build-up of fatty deposits on the
inner walls of the BVs that supply blood to the heart and brain.
Strokes can also be caused by bleeding from BVs in the brain or
from blood clots [5]. The causes of CVD are diverse but atheroscle-
rosis and hypertension are the most common. In addition, with ag-
ing comes a number of morphological and physiological changes
that alter cardiovascular function and lead to increased risk of CVD,
even in healthy asymptomatic individuals [6,7]. The common types
of CVDs, symptoms and their risk factors are mentioned in Table.
1. CVD is the leading cause of deaths worldwide, though, since the
1970s, cardiovascular mortality rates have declined in many high-
income countries [8]. Meanwhile, cardiovascular deaths and disease
have elevated at a faster rate in low- and middle-income countries
[9] and it has been estimated that over 80% of the world’s deaths
from CVDs occur in low- and middle-income countries [10-13].
Many people in these countries die younger from CVDs and other
non-communicable diseases, often in their most productive years.
On the basis of the global status of non-communicable diseases,
WHO reported that CVDs are the number one cause of deaths glob-
ally; as estimated, 17.3 million people died from CVDs in 2008,
indicative of 30% of all global deaths [14]. Of these deaths, the
Global atlas on CVD prevention and control, WHO has estimated
that 7.3 million were due to coronary heart disease and 6.2 million
were due to stroke [14,15]. Therefore, non-commu-nicable disease,
including CVD and diabetes are estimated to reduce GDP by up to
6.77% in low- and middle-income countries experiencing rapid
*Address correspondence to this author at the Department of Internal Medi-
cine, University of Iowa, Iowa city, 52242, USA;
E-mail: manaskumarnayakbiotech@gmail.com
economic growth, as many people die prematurely [16]. Mathers et
al. reported that CVDs (mainly from heart attacks and strokes) are
projected to remain the single leading cause of death and will in-
crease to reach 23.3 million by 2030 [8]. In addition, Lim et al.
analysed a systematic and comparative risk assessment of burden of
disease and injury attributable to risk factors and observed that each
year 9.4 million deaths or 16.5% of all deaths are caused due to
high blood pressures, among which 51% of deaths include stokes
and 45% of deaths attributed to CVDs [10]. Most CVDs can be
prevented by addressing risk factors such as tobacco use, unhealthy
diet, obesity, physical inactivity, high blood pressure, diabetes, and
raised lipid contents [7,17,18].
The recent advent of nanotechnology has had a tremendous
impact on many areas in science and engineering, especially in
advancing medical science and health care [19,20]. In nanotechnol-
ogy, engineered materials or devices are used for the smallest func-
tional organisation on the nanometer scale (1-100 nm) in atleast one
dimension [21]. The nanomaterials and nanodevices can interact
with biological entities at molecular levels with a high degree of
specificity and reactivity [22]. Thus, they can stimulate, respond to
and interact with target cells and tissues in controlled ways to in-
duce desired physiological responses while minimizing undesirable
effects. With all this potential, nanotechnology could have a revolu-
tionary impact on diagnosis and therapy of cardiovascular diseases
(CVDs) [19,20,22]. In this review, we provide an overview of the
most exciting advances in nanomaterials and nanodevices that have
been implemented as a therapeutic agent in the treatment and diag-
nosis of CVD.
2. RISK FACTORS FOR CARDIOVASCULAR DISEASES
(CVDs)
Behavioral risk factors such as unhealthy diet, physical inactiv-
ity, tobacco use and harmful use of alcohol are responsible for
about 80% of coronary heart disease (CHD) and cerbrovascular
disease (CD) [23]. These risk factors are responsible for increased
blood pressure, raised blood glucose and blood lipid levels and
caused overweight and obesity in individuals. The cessation of
tobacco use, reduction of salts in the diet, consuming fruits, vegeta-
bles, regular physical activity and avoiding harmful use of alcohols
Manasa K. Nayak
1873-4286/15 $58.00+.00 © 2015 Bentham Science Publishers
4480 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
have been shown to reduce the risk of CVDs. Moreover, the cardio-
vascular risk can also be reduced by preventing or treating hyper-
tension, diabetes, and raised blood lipids [24]. In addition, there are
a number of underplaying instigations such as globalizations, ur-
banization, population ageing as well as poverty, stress and heredi-
tary factors causes of the CVDs [25].
Anderson et al. [26] predicted the equations for several cardio-
vascular disease endpoints, which are based on measurement of
several known risk factors. The equations to predict the risk of
CVDs were developed considering myocardial infarction, coronary
heart diseases (CHDs), death from CHDs, CVDs and death from
CVDs and stroke. The equations demonstrated the potential impor-
tance of controlling multiple risk factors such as blood pressure,
total cholesterol, high-density lipoprotein cholesterol (H-DLC),
smoking, glucose intolerance, and left ventricular hypertrophy as
opposed to focussing or controlling single risk factor. Ahmed et al.
[25] reported that Asian Indians are known to be at a high risk for
cardiovascular disease (CVD), type-2 diabetes and metabolic syn-
drome (MetS) which is attributed to the ‘Asian phenotype’. Several
studies indicated that the MetS is closely related to insulin resis-
tance (IR) and also linked with iron overload. Increased serum fer-
ritin (SF) is often associated with measures of IR, such as elevated
blood glucose and insulin levels [27, 28]. With this connection,
Ewang-Emukowhate et al. [29] reported that genetic and environ-
mental factors together, play a role in the lipid patterns. Dyslipide-
mia in the MetS associated with insulin resistance is characterized
by an atherogenic lipid profile comprising increased low density
cholesterol (LDL-C), triglycerides and inclined numbers of small
dense low density lipoprotein particles. The pattern of dyslipidemia
varies across different ethic groups with increases in triglycerides
and a reduction in LDL-C being the commonest pattern in non-
Caucasians (South Asia and West African population). Gabrielsen
et al. investigated the mechanism underlying the relationships
among SF, adiponectin, and MetS in mice and human. Studies in
cell culture, demonstrated that iron plays a direct and causal role in
determining adiponectin levels and diabetes risk [27]. Epidemiol-
ogical studies provided the increased iron stores are a risk factor for
developing cardiovascular and metabolic abnormalities [28]. Al-
though mechanistic insights have been limited, in diabetes and
MetS, iron may contribute to risk following deposition in the liver,
skeletal muscle and pancreas, where it can enhance oxidative dam-
age, contribute to insulin deficiency and resistance [30]. However,
Toss et al. reported that several positive acute phase reactants, such
as C-reactive protein (CRP) and ferritin are accompanied by the
elevation of CVDs [31]. With this connection, He et al. [32] re-
ported that the relative risk (RR) existing in recurrent cardiovascu-
lar events or death associated with C-reactive proteins (CRP) within
72h from acute coronary syndromes (ACS) onset in a cohort and
secondary analysis of randomized controlled trials. Moreover,
Table 1. Types of cardiovascular diseases (CVDs), symptoms and risk factors.
Types of CVD Description Symptoms Risk factors
I. Coronary heart diseases
Ischemic heart disease (IHD); most
common type
(i) Heart attack;
(ii) Angina at chronic condition
High BP, high BC, tobacco use, unhealthy
diet, physical inactivity, diabetes,
advancing age, inherited disposition
II. Stroke Common form of CVD and three
categories:
(i) Ischemic stroke; (ii) hemorrhagic
stroke; (iii) Transient ischemic attack
Brain damage, leading to a
sudden impairments; weakness
often on one side of the body
High BC, tobacco use, unhealthy diet,
physical inactivity, diabetes, and
advancing age
III. Rheumatic heart dis-
ease and Rheumatic fever
Inflammation of the heart valves and
heart muscle caused rheumatic fever
(streptococcal bacteria); begins as a sore
throat or tonsillitis in children
(i) Shortness of breath, fatigue,
irregular heart beats, chest pain
and fainting.
(ii) Fever, pain and swelling of
the joints, nausea, stomach
cramps and vomiting
-
IV. Congenital heart
disease
Malformations of heart or central blood
vessel at birth or during gestation (e.g.,
hole in heart, abnormal valves, and
abnormal heart chambers)
Breathlessness or a failure to
attain normal growth and
development
Maternal alcohol and medicines use; ma-
ternal infection (e.g., rubella); poor mater-
nal nutrition; close blood relationship
between parents consanguinity
V. Peripheral vascular
disease
Peripheral arterial disease;
Two important forms;
(i) Atherosclerosis (ii) Abdominal aortic
aneurysm
- Long-standing high BP; Marfan
syndrome; tangential heart disorders,
syphilis, and other infectious and
inflammatory disorders
VI. Deep venous thrombo-
sis (DVT) and pulmonary
embolism
The blood clots in the leg veins, which
can dislodge and move to the heart and
lungs
- Surgery, obesity, cancer, recent childbirth,
use of contraceptive and hormone
replacement therapy, long periods of im-
mortality and previous episode of DVT
VII. Other cardiovascular
diseases
Tumors of the heart; vascular tumors of
the brain; disorders of heart muscle
(cardiomyopathy); heart valve diseases
- -
[BP: Blood pressure; BC: Blood cholesterol]
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4481
Lipoprotein (a) (Lp (a)), considered an emerging risk factor by
National Cholesterol Education Programme’s Adult Treatment
panel III (NCEP ATP III), has been implicated in the development
of the premature atherosclerotic disease seen in South Asians [33].
Serum uric acid (UA) is implicated and often been considered as
one of the potential risk factors underlying the development of both
MetS and CVDs [34, 35]. Chatterjee et al. reported that the levels
of novel risk factors namely high sensitivity C-reactive protein
(hsCRP), ferritin, Lp (a) and UA in metabolic syndrome (MetS)
subjects with and without coronary artery disease (CAD) and found
out their association with components of MetS as well as other
traditional risk factors, which could be helpful in preventing future
morbidity and mortality and thereby reducing the burden of CVDs
[36].
3. CARDIOVASCULAR DISEASES (CVDs) AND INFLAM-
MATION
The role of inflammation has become well established over the
past decade or more in theories describing the CVD process [37].
Inflammation provides a common link between many risk factors
for atherosclerosis and altered arterial biology [38]. It has been
reported that modification of these risk factors can exert a clinical
benefit by reducing inflammation and its effects [39]. Emerging
evidence from clinical trials supports the use of inflammatory status
as a guide to therapy that can reduce cardiovascular diseases. Abso-
lutely, the concept of inflammation has materialized from the do-
main of theory and laboratory investigations to assume a promising
role as a useful tool in the clinic to aid the prevention and manage-
ment of cardiovascular disease [40]. The CVD and related disorders
are characterized by an inflammatory component at some stage of
the pathology. The risk factors for CVDs give rise to a variety of
stimuli that draw out the secretion of leukocyte soluble adhesion
molecules such as E-selectin, which promote the attachment of
monocytes to endothelial cells (endothelial cells also activate and
express a variety of adhesion molecules) and facilitate monocytes to
migrate into the sub-endothelial space. Moreover, in the sub-
endothelial space, the transformation of monocytes into macro-
phages and the uptake of cholesterol lipoproteins are thought to
emerge fatty streaks. Furthermore, injurious stimuli may continue
the accumulation and attraction of macrophages, mast cells, and
activated T cells within the growing atherosclerotic lesion. Fig. (1)
shows mechanism of cardiovascular diseases (CVDs) and related
inflammation. The non-fatal incidents of stroke and myocardial
infarction that result from a thrombus blocking the cerebral or
coronary vessels, respectively, result in ischemic injury that is fol-
lowed by reperfusion of the infarcted area. During the reperfusion,
leukocytes are activated and release a variety of oxidative stress-
response molecules and pro-inflammatory lipid and peptide media-
tors [41].
Oxidized low-density lipoproteins (LDL-oxidized) may be one
of several factors that donate to loss of smooth muscle cells through
apoptosis in the atherosclerotic plaque cap. Discharge of metallo-
proteinase and other connective tissue enzymes by activating
macrophages may break downcollagen, weakening the cap and
making it prone to rupture [42]. This crack-up of the atherosclerotic
plaque induces thrombosis. Therefore, every stage of atherosclero-
sis is believed to involve cytokines, other bioactive molecules, and
cells that are characteristics of inflammation [43, 44].
Since inflammation is believed to have a role in the pathogene-
sis of cardiovascular events, the markers of inflammation such as
lipids and peptide mediators, cytokines, macrophages, mast cells,
and activated T cells and other bioactive components are essentials
for prediction of CVDs. [45].
The updated information about inflammations of CVD such as
causative agents, sequential events, and possible mechanisms will
benefit in diagnostics and clinical applications of CVDs.
4. CONVENTIONAL THERAPEUTICS STRATEGIES FOR
CVDs
Despite of all advances in pharmacological and clinical treat-
ment, CVDs and their related causes are leading cause of morbidity
and mortality worldwide.
Fig. (1). Cardiovascular diseases and related inflammation. The risk factors give rise to a variety of stimuli, which draw out the secretion of leukocyte
soluble adhesion molecules such as E-selectin. The adhesion molecules further promote the attachment of monocytes to endothelial cells and facilitate mono-
cytes to migrate into the sub-endothelial space. In the sub-endothelial space, the transformation of monocytes into macrophages and the uptake of cholesterol
lipoproteins are thought to emerge fatty streaks. Furthermore, injurious stimuli may continue the accumulation and attraction of macrophages, mast cells, and
activated T cells within the growing atherosclerotic lesion.
Endothelial Cells
E-Selectin
Rolling
Adhesion
Transmigration
Endothelial Space
Macrophage
Lipoprotein Uptake
Mast Cells
T-C e ll
T-Cell activated
Chemokines
Activation
4482 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
4.1. Molecular Therapeutic Approaches
A range of molecular therapeutic advance strategies, including
cell transplantation and stem cell therapy, gene delivery or therapy,
tissue factor inhibitors, micro RNSs or other small molecules have
been researched to treat CVDs [46].
4.1.1. Cell Transplantation and Stem Cell Therapy
Stem cell-based therapies have rapidly emerged as a potential
novel therapeutic approach in CVDs [47]. Bone marrow-derived
progenitor cells and other progenitor cells can differentiate into
vascular cell types, restoring blood flow [48, 49]. They may con-
tribute to the regeneration of infarcted myocardium and enhance
neovascularization of ischemic myocardium [48]. Several research-
ers have been reported that autologous bone marrow cells (BMCs)
transplanted into ventricular scar tissue may differentiate into car-
diomyocytes and restore myocardial function [50-54]. In contempt
of all advancements in the therap eutic use of stem/progenitor cells
for ischaemic heart diseases. The effect of the implanted cells on
heart function is probably occurring at a very low rate, due to un-
certainties in proliferation and differentiation potential of cardiac
cells [55]. Moreover, there is strong evidence that endothelial cells
are renewed by bone marrow- derived progenitor cells [56], but the
idea that cardiomyocytes are renewed by such cells is vigorously
debated [49].
4.1.2. Gene Delivery or Therapy
The advancement of the molecular mechanisms in CVDs has
increased dramatically in recent years [57]. To understand the mo-
lecular pathology of CVDs, the evolution of vector technology has
significant potential to target the underlying molecular processes
affecting failing cardiomyocytes [58]. Gene therapy offers an at-
tractive alternative to current pharmacological therapies and may be
beneficial in treatments for CVDs [59]. In addition, advances in
recombinant DNA technology, including gene transfer, have stimu-
lated hope that this technology can be used to improve the practice
of cardiovascular medicine [58].
The development of molecular genetics involvements to treat
CVDs depends on technical advances in the development of meth-
ods of gene delivery. The objective of various developed methods
of gene transfer is to achieve a long-term, highly efficient, and tar-
geted expression in relevant cells of the cardiovascular system [60].
The modes of gene transfer include; viral vectors (adenoviruses and
retroviruses), and nonviral vectors (cationic liposomes, polymers,
and injection of plasmid DNA) and delivery method (direct,
transvascular, and ex vivo) have been used. Moreover, gene therapy
with isoforms of growth factors such as vascular endothelial growth
factors (VEGFs), fibroblast growth factors (FGFs) and hepatocyte
growth factors (HGFs) induces angiogenesis, decreases apoptosis
and leads to protection in the ischemic heart [61]. Gene therapy
coding for antioxidants, heat shock proteins (HSPs), mitogen acti-
vated protein kinase (MAPK) and numerous other anti apoptotic
proteins have demonstrated significant cardio-protection in animal
models [62].
However, it has been reported that a cardiovascular gene ther-
apy for stimulating angiogenesis in patients, the peripheral vascular
disease has been initiated. Moreover, the application of gene trans-
fer to CVDs has proceeded at a slower rate [58, 59]. In addition,
lack of persistence of gene expression may result from cytolytic
responses directed against infected cells.
4.1.3. Tissue Factors (TF) Inhibitors
Tissue factor, formerly known as thromboplastin, is the key
initiator of the coagulation cascade, has been implicated in the
pathogenesis of several cardiovascular disorders [63]. Elevated
levels of TF are observed in patients with CVDs and related dis-
eases. TF may certainly be involved in the pathogenesis of athero-
sclerosis by promoting thrombus formation and act through diverse
signal transduction mechanisms, including MAP kinases, PI3-
kinase, and protein kinase C [63, 64]. In addition, various cytoki-
nes, growth factors, and biogenic amines have been recognized to
induce TF expression in endothelial cells (ECs), vascular smooth
muscle cells (VSMCs), and monocytes [64].
To maintain steady-state and healthy conditions, several inhibi-
tory pathways may be practiced to counteract the activity of the TF
mediated coagulation system [64]. Molecular approaches such as
ribozymes or antisense oligonucleotides specifically inhibit TF
production. Monoclonal or polyclonal anti-TF antibodies directly
target and inactivate the TF protein. Recombinant anticoagulant
protein interferes with the TF complex, leading to the formation of
a quaternary inhibitory complex and thus, inactive the TF forma-
tion. Although, several promising therapeutic strategies have been
developed for targeting the action of TF; at present, the relative
contribution of TF to thrombus formation and/or propagation and
associated with atherogenesis is still debated [64].
4.1.4. MicroRNAs (miRNAs)
MicroRNA (abbreviated miRNA) is a small non-protein coding
regulatory RNA molecules (containing about 20-23 nucleotides)
that exist in virtually all organisms and which regulates in RNA
silencing and post translational regulation of gene expression [65].
Moreover, they are highly evolutionary conserved, suggesting a
superior role in essential biological [66]. Details about the biogene-
sis and regulation of cardiovascular miRNAs have been reviewed
[67]. In brief, initial primary miRNAs (pri-miRNA) are processed
to form precursor miRNAs (pre-miRNA) and further processed by
various factors (such as, RNase type-III, Ribonuclease Dicer) into
small 20-23 nt long miRNA duplexes. Finally, miRNAs are in-
volved in silencing the gene expression at the post translational
level with the result of mRNA degradation or by translational inhi-
bition finally leading to target protein repression. These miRNA
expression patterns change in various CVDs, such as myocardial
infarction, cardiac hypertrophy and heart failure [68, 69]. This has
raised the possibility that miRNAs may be probed in the circulation
and can serve as novel diagnostic markers [70]. It has been quickly
recognized that miRNAs can be efficiently inhibited for prolonged
periods by antisense technologies. These technilogies have fueled a
growing interest in the inhibition of specific miRNAs (referred to as
antimiRs) and triggered enthusiasm for miRNAs as novel therapeu-
tic targets [71].
Disease-inducing cardiac microRNAs can be persistently si-
lenced in vivo through the systemic delivery of antimiRs, allowing
for the direct therapeutic modulation of disease mechanisms [71].
However, nature of the stability of miRNAs that circulate in the
bloodstream raised potential challenges of microRNA-based ap-
proaches drug-based therapies [72-76].
4.2. Other Small Molecules
4.2.1. Microparticles (MPs)
Microparticles (MPs) are membrane vesicles released from
many different cell types [77]. There are different pathways in-
volved in the MPs generation (i.e., cell activation and apoptosis).
MPs vary in protein composition, size and phospholipids contents,
and have a robust pro-inflammatory effect and promote coagulation
cascade pathways [78]. In addition, circulating levels of MPs is
augmented in pathogenesis of cardiovascular diseases [79]. There-
fore, MPs inhibited based therapies may be followed in the under-
standing of the pathogenesis, prevention and treatment of these
CVDs. Treatment with antioxidants, (e.g., Vitamin C or Carvedilol)
decreases circulating endothelial MPs in patients with heart failure
[80].
Thus, several researchers claimed for the treatment and also
formulated therapeutics of CVD which affect MPs numbers. How-
ever, these effects on MPs contributing to the therapeutic action
remains to be established [80,81].
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4483
Table 2. A global vision of potential therapeutics for CVDs.
Potential Therapeutics Study design Results References
Conventional therapeutic strategies for CVDs - - -
High-density lipoprotein cholesterol (HDL-C) - - -
HDL-C and CVDs: four prospective American
studies
Men and women (aged between 30 and 69
years)
HDL-C levels unrelated to non-
CVDs mortality
[81]
Raising HDL with CETP inhibitor HDL-C levels and 3H-tracer macrophages Significantly reduced TG, blood
glucose and plasma insulin levels
[84]
Leukotriene (LT) modifiers - - -
5-LOX inhibitor inhibits neuronal apoptosis
and focal cerebral ischemia
Adult male Sprague–Dawley rats Neuroprotection against ischemic
stroke
[94]
Zileuton on inflammatory injury to myocar-
dium
3mg/kg zileuton was given to rat model Significant decrease in myocardial
apoptosis
[95]
Micro RNA (miRNA) - - -
miRNAs in atherosclerosis in vivo -
Elevated miR-155 levels in athero-
sclerotic lesions
[68]
MicroRNA-126-5p - Rescued EC proliferation and limits
atherosclerosis
[69]
miR-181 family - Vascular inflammation [70]
Angiotensin-converting enzyme -2 (ACE-2) - - -
ACE2/Ang-(1-7)/Mas pathway Used three-month and eight-month transgenic
mice
Prevents brain from ischemic injury [107]
Nanotechnology for therapeutic strategies for
CVDs
- - -
Streptokinase Target-sensitive liposomes and evaluation
with in vivo and in vitro studies
Treatment of thromboembolism [171]
Functionalized nanoporticles (PLGA) nanoparticles Cardio-protection and clinical ther-
apy for ICD
[162]
Functionalized nanofibrous scaffold - - -
Elctrospun matrices for cardiomyogenic stem
cell differentiation
For differentiation of ESCs towards a cardio-
myogenic lineage
Promoted differentiation and
maturation of cardiomyocytes
[186]
Nanofibrous scaffold Nanofibrous scaffold from Hemoglo-
bin/gelatin/fibrinogen (Hb/gel/fib)
Regeneration of the ischemic myo-
cardium
[183]
Tissue engineered bioprosthetic heart valve Heart valve leaflets/scaffold Feasible to construsct allogenic
heart valve tissue
[190]
Tissue engineered Biomaterials for treatment
of CVDs
- - -
PLGA-(70/30) microtubular orientation-
structured blood vessel
Cell affinity of the scaffolds was evaluated in
vitro
Cells was found and showed high
viability and rapid proliferation
[180]
PPLA scaffolds to better engineered blood
vessels of small-diameter
Better engineered blood vessels of small-
diameter
Facilitate blood-vessel regeneration [182]
Co-electrospinning of PLGA, gelatine, and
elastin (PGE) for vascular tissue engineering
Tune-fine fibrous samples were prepared Potential in vascular tissue engi-
neering
[183]
Hydroxyl-functionalized PCL and loaded with
VEGF
Scaffolds were prepared by coaxial
electrospinning
Bioactive scaffolds for TE applica-
tions
[187]
4484 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
(Table 2) Contd….
Potential Therapeutics Study design Results References
PCL tubular freeze-dried scaffolds for small
diameter blood vessel replacements
A PCL tubular freeze-dried scaffold was
fabricated with freeze-dried composite struc-
ture
For a small diameter vascular pros-
thesis
[192]
PEG - QK (Gln-Lys) based composite RGD sequences and the novel Both in vitro
and in vivo in a mouse cornea micropocket
angiogenesis assay was performed
Provided an angiogenic signalling [194]
Biomimetic PEG based hydrogels A collagen type I-derived peptide (GIA) con-
taining PEGDA (PEGDA-GIA) was synthe-
sized
Formed a capillary-like networks [195]
hCASMCs seeded on polyurethane scaffold Cell viability as well as growth has been as-
sessed
Elastomeric tissue engineering
scaffolds
[201]
Gradient nanofibrous for vascular tissue
engineering
Constructed a biomimetic were characterized
by seeding HUVECs
Heparinozed CS/PCL nanofibrous
creates vessel grafts with similar
natural blood vessels
[199]
Effects of endothelial cell adhesion to SPUUs
containing amino acids
MTT tests as well as cell adhesion, spreading
and viability was determined
Potential for CVDs and angiogene-
sis
[200]
Porous SF scaffolds for potential use as
vascular grafts
In growth and neovascularisation were also
examined in vivo by subcutaneous implanta-
tion in rats
Potential vascular grafts
[202]
[CETP: Cholesteryl ester transfer protein; TG: triglycerides; 5-LOX: 5-Lipoxygenase; ICD: Ischemic cardiovascular diseases; PLGA: Poly (lactide-co-glycolide); PCL: poly(-
caprolactone); TE: Tissue engineering; hCASMCs: Human coronary artery smooth muscle cells; HUVECs: Human umbilical vein endothelial cells; SPUUs: segmented poly (urea)
urethanes; SF: silk fibroin]
4.2.2. High-Density Lipoprotein Cholesterol (HDL-C)
Higher plasma levels of high-density lipoprotein cholesterol
(HDLC) and decreased incidence of cardiovascular disease end-
points have been observed in epidemiological studies conducted by
several groups of researchers [82-84]. Therefore, more successful
therapeutic interventions for CVD, have been reduced plasma con-
centrations of low-density lipoprotein cholesterol (LDL-C) and the
inverse relationship of HDL-C raising therapy as a novel target [85-
92]. The underlining mechanism through which raising HDL-C
levels may exert its atherosclerotic effects is due to inhibition of
cholesteryl ester transfer protein (CETP) [85]. Rader et al. [92]
reported that HDL is a key component of predicting cardiovascular
risk. However, in spite of its properties, rational with atheroprotec-
tion, the relation between HDL and atherosclerosis is uncertain.
Human genetics and failed clinical trials have created doubt about
the HDL hypothesis. Nevertheless, drugs that raise HDL-C concen-
trations, cholesteryl ester transfer protein (CETP) inhibitors, are in
late stage clinical development, and other approaches that enhance
HDL function, such as reverse cholesterol transport, are in early
stage clinical development. Remaley et al. briefly discussed the
currently established the two main classes of drugs that raise HDL-
C is nicotinic acid and fibrates [93]. Nicotinic acid is more effective
in raising HDL-C, wh ereas fibrates are more effective in decreasing
elevated triglyceride (TG) levels, which are often inversely associ-
ated with HDL levels.
However, both drugs have some of their limitations such as
uricosuria, increased glucose tolerance, flushing for nicotinic acid,
and problematic pharmacokinetic interactions for fibrates, there-
fore, limits their use.
4.2.3. Leukotriene (LT) Modifiers
Leukotrienes (LT) are short-lived lipid mediators that have
potent pro-inflammatory biological activities. They may form at the
nuclear membrane of inflammatory cells, such as macrophages,
neutrophils, eosinophils and mast cells in response to diverse im-
mune and inflammatory stimuli [95]. Several evidences from ex-
perimental and genetic studies suggested that there is an existence
of potential link between the LT signalling cascade, and the patho-
genesis/progression of atherosclerosis [94-105]. LTs are then se-
creted into the extracellular space through specific transporters [95,
96]. Owing to their anti-inflammatory properties, LTs have been
used for the primary therapeutics in asthma management for several
years. Although blocking the inflammatory component of human
disease is a long-lasting and established concept, the use of LTs
modifiers in treating the inflammatory component of CVDs (athe-
rosclerosis, myocardial infarction, stroke and aortic aneurysm) has,
surprisingly, only been seriously reflected in the past few years [95-
97]. The LTs modifiers such as 5-lipoxygenase (5-LO) inhibitor
(ziluton), the leukotriene receptor antagonists (pranlukast, zafirlu-
kast and montelukast) and two members of the 5-LO- activating
protein (FLAP) antagonist family (BayX-1005/DG-031 and MK-
0591) that underwent extensive preclinical development [96]. Fur-
ther experimental and clinical studies are needed to determine the
potential therapeutic strategies targeting the LT pathway in CVD to
increase a potential use of these drugs in the context of subclinical
atherosclerosis [105].
4.2.4. Angiotensin-Converting Enzyme 2 (ACE2)
It has been well established that the rennin-angiotensin system
(RAS) is an important regulator of cardiovascular function and has
an important role in the pathophysiological development of various
CVDs [106,107]. Shi et al. [108] reported that angiotensin-
converting enzyme (ACE) is a major target in the treatment of
CVDs. Moreover, angiotensin-converting enzyme-2 (ACE-2), the
homolog of ACE, which promotes the degradation of angiotensin II
(Ang II) to Ang (1-7) has been recognized recently as a potential
therapeutic target in the management of CVDs. More recently,
Reddy Gaddam et al. [109] reported that ACE involved in the syn-
thesis of bioactive components of RAS and the main active peptides
of the RAS include angiotensin II (Ang II), Ang III, Ang IV, and
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4485
angiotensin-(1-7) [Ang-(1-7)] among which Ang II and Ang-(1-7)
are much more important in health and disease. More specifically,
the hydrolysation of angiotensin (Ang) I to produce Ang-(1-9),
which is subsequently converted into Ang-(1-7) by a neutral en-
dopeptidase and ACE. The Ang-(1-7), so formed is considered to
be a beneficial peptide of the RAS cascade in the cardiovascular
system and control cardiovascular physiology. Zheng et al. [110]
investigated the effect of angiotensin (Ang) converting enzyme-2
(ACE-2)/Ang-(1-7)/Mas receptor pathway (component of RAS) on
the beneficial effect in ischemic stroke. The results found that ACE-
2/Ang-(1-7)/Mas axis prevents the brain from ischemic injury via
the Nox/ROS signalling pathway. However, it has been difficult to
understand the complex relationship of two-arm RAS hypothesis
(of ACE-Ang II-receptor and ACE2-Ang(1-7)-Mas axis) [111].
4.2.5. Thrombolytic Agent
Vascular thrombosis (VT) or thrombolytics play an important
role in several diseases and is a major clinical problem, particularly
in developed Western countries. Indeed, VT (thrombolytics) ac-
counts for about half of all deaths in these countries as a result of
consequential myocardial infarction, ischemic stroke, pulmonary
embolism (PE) and likewise other vascular obstructions (peripheral
arterial diseases). The process of fibrinolysis acts by activation of
plasminogen to plasmin; plasmin splits fibrinogen and fibrin and
lyses the clot, which then allows reperfusion of the ischemic brain.
The best way to improve patient survival and decrease morbid-
ity is prompt detection and treatment of thrombosis with throm-
bolytic agent(s). A variety of thrombolytic agents such as strepto-
kinase (SK), urokinase and tissue plasminogen activators (t-PA) are
pharmacologically active and available. These thrombolytic agents
comprise proteolytic components of the blood clotting cascade, and
as they circulated throughout the cardiovascular system they do not
selectively target specific organs or tissues. The systemic side ef-
fects of these agents such as fibrinogenolysis and bleeding [112].
These are currently in clinical use for dissolving arterial thrombi,
particularly in cardiac blood vessels. These thrombolytic agents
work by activating the protein, plasminogen into plasmin [113].
Streptokinase (SK) is one of the most commonly used throm-
bolytic agents for the treatment of thromboembolism. However,
short half-life of the SK due to rapid inactivation of plasminogen
activators such as plasminogen activator inhibitor-1 (PAI-1) and
circulating antibodies requires administration of higher dose which
results in various side effects, including systemic haemorrhage due
to activation of systemic plasmin. Various techniques have been
employed to enhance stability of plasminogen activators against
these components and hence to increase the half-life, which ulti-
mately increase the accumulation at the site of thrombus. PEGy-
altion and novel carrier constructs, including liposome and polym-
eric particles are most frequently used [114]. Murray et al. [115]
reported that thrombolytic agents such as streptokinase (SK), re-
combinant tissue-type plasminogen activator (rt-PA) among prom-
ising agents under development and in clinical trials. SK is nonfi-
brin-specific, has a longer half-life than tissue-type palsminogen
activator (t-PA). SK avoids re-occlusion and is degraded enzymati-
cally in the circulation. However, rt-PA is more fibrin-specfic and
has clot-dissolving activity and is metabolized during the first pas-
sage in the liver. So far the fibrin-specific rt-PA is the only agent to
be approved for use in stroke. This may be due to its short half-life
and its absence of any specific amount of circulating fibrinogen
degradation products, thereby leaving platelet functionally intact.
More specifically, Campbell et al. [116] reported that recomibinant
thrombolytic peptides are mainly represented by recombinant forms
of tissue-type palsminogen activator (t-PA) (a proteolytic enzyme)
that catalyzes the conversion of plasminogen into active plasmin,
which then functions to dissolve clots. The three clinically suitable
recombinant thrombolytic peptides are alteplase (t-PA), reteplase
(r-PA), and tenecteplase (TNK). r-PA and TNK have been structur-
ally modified from native t-PA to increase their half-life and fibrin
specificity. Moreover, thrombolytic therapy is the treatment of
choice for ischemic stroke in patients who present 3 hours follow-
ing the onset of symptoms. Furthermore, thrombolytic therapy is
used to restore function to stenotized central venous access devices
as well as occluded hemodialysis access grafts. Zhang et al. [117]
reported that the addition of a neuroprotective agent can increase
the effectiveness of thrombolytic therapy, increase the therapeutic
time window, and reduce cerebral ischemia-reperfusion injury. It is
hoped that thrombolytic agents with neuroprotective effects can be
developed for clinical use. Vaidya et al. [118] developed target-
sensitive liposomes which were prepared by using moderate affinity
peptide c (RGDfK) acylated with palmitic acid. In vitro results
revealed that target-sensitive liposomes beneficial in the targeted
delivery of thrombolytic agents to the site of blood clot where acti-
vated platelets are embedded. However, for in vivo application,
targeting ligand with higher affinity to the target site would be more
effective than moderate affinity ligand. Therefore, c (RGD) peptide
[CNPRGDY (OEt) RC] has been investigated and found to have a
higher affinity for GP IIb/IIIa receptors on the platelet surface as
compared to other receptors. Thus, developed liposomes were
found to release streptokinase in vitro following binding with acti-
vated platelets. In addition, the prepared liposomes were character-
ized for in vivo targeting by intravital microscopy and therapeutic
efficacy was evaluated using human clot inoculated rat model and
revealed higher accumulation in the thrombus area. In vivo throm-
bolytic study was performed in the human clot inoculated rat
model. Moreover, the overall results of the study showed that tar-
get-sensitive liposomes dissolved 28.27±1.56% thrombus as com-
pared to 17.18±1.23% non-liposomal streptokinase. Du et al. [119]
synthesized a hybrid hydrogels based on a genetically modified tax
interactive protein-1 (TIP1) by introducing two or four cysteine
residues in the primary structure of TIP1. The cysteine residues
were cross-linked with four armed- poly (ethylene glycol) (PEG)
capped with maleimide residues (4-armed-PEG-Mal) to form hy-
drogels. Further, AD293 cells were allowed to divide and displayed
a polyhedron or spindle-shape during 3-day culture period. The
cells were recovered from the TIP1 2C RGD gel grew well in the
conventional 2D cell culture, suggesting its great potential for
large-scale culture.
5. NANOTECHNOLOGY ASPECTS OF THERAPEUTIC
STRATEGIES FOR CVDS
Nanotechnology represents a convergent discipline of various
research areas, such as biology, chemistry, physics, mathematics
and engineering is becoming complicated [120]. Recent develop-
ments in nanotechnology have created considerable potential to-
ward diagnosis and therapeutic treatments for CVDs. Fig. (2) high-
lights the nanotechnology approaches for the benefits of CVDs that
will be discussed in this review. Though, the use of nanotechnology
in the treatment and diagnosis of CVD remains largely unexplored.
Nevertheless, cardiovascular nanomedicine is likely to face and
address current challenges in CVDs. It will also improve detection
and therapy by advancing techniques, to improve delivery of drugs
and for tissue regeneration [121]. Therefore, the main objective of
this review article is addressing the problems associated with con-
ventional therapeutics such as nonspecific effects and poor stability
and to focus on nano-carriers advancement for the benefits of
CVDs.
Nanotechnology mainly provides following benefits for CVDs
5.1. In Vivo Imaging Technique:
Offers the visualization of cellular functions using “smart” im-
aging agents or targeted imaging nanoprobes (especially magnetic
nanoparticles, and quantum dots) rather than biomarkers in tradi-
tional imaging techniques.
4486 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
5.2. NanoBiosensors and In Vitro Diagnostics:
Improved analytical devices/ Biomedical or Biological Micro-
Electro-Mechanical Systems (BioMEMS) for accurate detection of
small quantities of disease biomarkers is critical for the clinical
diagnosis of disease.
5.3. Controlled D rug Delivery or Targeted Therapeutics:
Nanoscale delivery of drugs enhances therapeutic efficacy and
develop an effective therapeutic modality.
5.4. Tissue Engineering:
Nanotechnology can provide an engineered biocompatible ma-
terials resembling extracellular matrix (ECM), support for building
new and implanting tissue [122,123].
5.5. In Vivo Imaging Technique
The lesions in atherosclerosis represent the most important
cause of acute cardiovascular incidents and best described as vascu-
lar inflammation [124]. The hydrolytic enzymes secreted by differ-
ent cell types (monocyte-derived macrophages and T lymphocytes)
during cardiovascular inflammation may play a central role in dif-
ferent stages of atherogenesis. Conventional imaging techniques
such as development of enzyme (Cathepsin B as a model prote-
olytic enzyme) sensing near-infrared imaging probes and become
possible due to a developed imaging technique known as fluores-
cence-mediated tomography (FMT). Moreover, FMT technique
shares sensing of picomole to femtomole quantities of fluoro-
chromes in deep tissues at macroscopic scale [125]. Despite the
encouraging results of this technique, several points will require
further investigation. The most importan t is the animals routinely
develop accelerated and lively inflammation-rich atherosclerosis
leading to aortic aneurysms [125, 126]. Therefore, many molecular
imaging studies of atherosclerosis target inflammation, involve a
critical process underlying the progression and rupture of athero-
sclerotic lesions [127]. In addition, the diagnosis, monitoring, and
prognostication of CVDs are based on techniques that measure
changes in metabolism, blood flow, and biological function [125-
127].
Nanoscale contrast agents have emerged as multifaceted ap-
proaches that can be used to label and characterize the early stages
of disease before the development of pathological symptoms. Con-
trast generating nanomaterials for cardiovascular imaging include
radioactive, fluorescent, paramagnetic, super-paramagnetic, elec-
tron-dense and light-scattering particles [128].
5.5.1. Nanoparticles (NPs) -Enhanced Imaging
Nanoparticles (NPs) are emerging as potentially powerful
probes for in-vivo imaging in medical and biological diagnostics
[129]. They can fulfill a number of critical requirements required
for imaging techniques. The NPs are not influenced by various local
in-vivo environments such as ionic strength, pH, solvent polarity or
temperature. Moreover, they can easily dispersible, resist aggrega-
tion and form stable imaging agent. Ideally, these NPs are suitable
for long-term quantitative imaging at low doses and can be safely
cleared from the body after imaging is complete [129].
5.5.1.1. Magnetic Nanoparticles (MNPs)
The magnetic nanoparticles (MNPs) are classified (based on
their size) as magnetic iron oxide nanoparticles (MIONs, m), su-
perparamagnetic iron oxide nanoparticles (SPIONs, hundreds of
nm), and ultra-small paramagnetic iron oxide nanoparticles (USPI-
ONs, <50 nm) [130]. These MNP-based probes have been devel-
oped for Magnetic Resonance Imaging (MRI) to achieve high tissue
contrast and to improve the imaging sensitivity [131]. Moreover,
they have been directed imaging and therapy of atherosclerosis,
restenosis and related cardiovascular conditions. The superpar-
amagnetic contrast agents (SPIONs) predominately magnetite
(Fe2O3/Fe3O4), typically enhance and produce dark contrast [130].
The SPIONs encapsulated porous silica in a single unit enhanced
contrast at atherosclerotic plaques [132].
To fulfill the high resolution and high sensitivity requirements
for in-vivo imaging applications, biomimetic nanomaterial conju-
gated MNPs contrast agents with improved magnetic and physico-
chemical properties have been developed [133]. PLGA is usually
used in the construction of biomimetic materials and has extensive
application in medical imaging technology. Few reports have em-
ployed a new type of molecular probe in the treatment as well as in
the diagnosis of the thrombi. Zhou et al. constructed Fe3O4-based
poly (lactic-co-glycolic acid) (PLGA) nanoparticles to use in the
detection of thrombi and in targeted thrombolysis using MRI moni-
toring [134]. These biomimetic PLGA conjugated MNPs can serve
as a potential dual function tool in the early detection of thrombi
and in the dynamic monitoring of the thrombolytic efficiency using
MRI at the molecular level [134].
Macrophages, key effector inflammatory cells in atherosclero-
sis, abound in coronary plaques that have caused sudden cardiac
Fig. (2). The possible nanotechnology approaches in the therapeutics of CVDs.
Nanotechnology
as Therapeutic
strategies of
CVD
1.In vivo Imaging
technique
3.Controlled Drug
delivery or Targeted
therapeutics
2.NanoBiosensor
s and in vitro
Diagnostics
4.Tissue
Engineered
Biomaterials
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4487
death. Imaging of macrophages is an appealing approach to detect
inflammation in plaques prone to clinical complication. Dextran-
coated magnetic nanoparticles (MNPs) which are composed of
SPIONs (core) that induces strong MRI contrast and can easily
detect inflammatory cells (macrophages) at and around plaques
[135]. In addition, fibrin an attractive target for thrombosis (both
arterial and venous) imaging. The thrombin-mediated cleavage of
fibrinogen yields fibrin monomers, which then polymerize and
undergo cross-linking to form a stable clot. A recent progress in
fibrin imaging is the advancement of fibrin-targeted nanoparticles
(e.g., SPIONs) for computed tomography (CT) molecular imaging
of thrombus. Further, in vivo analysis with this agent could develop
the ability of CT to diagnose pulmonary embolism, stroke, or acute
coronary syndromes [136,137].
5.5.1.2. Quantum Dots (QDs)
One of the fastest moving and most exciting interfaces of
nanotechnology is the use of quantum dots (QDs) in biology [138].
Quantum dots (QDs) are tiny light-emitting particles on the
nanometer scale, and are emerging as a new class of fluorescent
labels in biology and medicine. In comparison with organic dyes
and fluorescent proteins, they have unique optical and electronic
properties [139]. They have proven themselves as powerful fluores-
cent probes, especially for their long-term, multiplexed and high
fluorescence quantum yields, high photostability, are a popular
choice for fluorescence imaging applications [140]. The fluorescent
quantum dots (QDs) emit light over a broad range from near-
ultraviolet to mid-infrared and have been used in contrasting agents
in CVDs [85]. Another important consideration for in vivo applica-
tions of QDs reducing the blood concentration and easily cleared
from the bloodstream [141]. Moreover, fluorescent QDs will pro-
vide important information in the rational design of biocompatible
drug carriers and will serve as a superior alternative to magnetic
and radioactive imaging contrast agents in preclinical drug screen-
ing, validation and delivery research [140]. So far, CdSe/ZnS and
CdTe/ZnS QDs are among the most extensively studied QDs for in
vivo imaging, due to their develop synthetic procedure and easily
available [142]. Concurrently, there are also several studies using
CdTe/CdS, PbS, and CdHgTe QDs, which are appealing for in vivo
applications because of their Near-infrared (NIR) emission [143-
145].
The ability to make QDs water soluble and target them to spe-
cific biomolecules potent surface functionalization is essential. In
addition, particularly for those QDs synthesized via the organomet-
allic route, surface modification of QDs can reduce the levels of
toxicity (e.g., Cd) [142]. The surface modification of bioconjugated
QDs has led to promising applications in cellular labelling, deep-
tissue imaging, and assay labelling and as efficient fluorescence
resonance energy transfer donors [138]. For example, carboxylate-
conjugates QDs (a mutant of the bioluminescent protein luciferase)
have a greatly enhanced sensitivity in small animal imaging. The
functionalized and bioconjugated QD probes can emit long-
wavelength bioluminescent light in cells and in animals, even in
deep tissues, and are suitable for multiplexed in vivo imaging [146].
Liu et al. fabricated surface functionalized QDs through covalent
modification via simple carbodiimide coupling chemistry. The sur-
face functionalization of QDs can be achieved by incorporating
ligand dihydrolipoic acid (DHLA), a short poly (ethylene glycol)
(PEG) spacer, and with an amine or carboxylate terminus. The
functionalized QDs (DHLA-PEG-ligand) produced aqueous de-
rivatizable QDs with small hydrodynamic size, low nonspecific
binding, high quantum yield, and good solution stability across a
wide pH range for cell-labeling applications [147]. In addition to
PEG, other polymer coating or QD-entrapped materials such as
poly (lactic-co-glycolic acid) PLGA and liposomes have also been
investigated because of their increased stability and reduced pho-
tooxidation and photobleaching in an in vivo experiments [142,
148]. Recently, Cao, et al. [149] developed a long term and sustain-
able QDs-functionalized with amphiphilic polymer with hydropho-
bic inner core, named as N-succinyl-N’-octyl nanomicelles (SOC),
used to incorporate oil-soluble PbS for tracking in an in vivo local
conditions. [149,150].
5.3. NanoBiosensors and In Vitro Diagnostics
Biosensor is an analytical device that accounts a biological
perception system to target molecules. This device can be conjoined
to a physiochemical transducer which transforms recognition into a
measurable amplified output signal in an appropriate format [151].
The establishment and advancement of micro- and nanoscale tech-
nologies for biology has a great potential to lead to the development
of next generation biosensors with improved sensitivity with re-
duced costs [151]. In addition, usually nanomaterials are exploited
to enhance the sensitivity of sensors, as they are easy to functionali-
ties with the appropriate sensing probes, and also act as signal
transducers. By restraining the material into the nanoscale dimen-
sion the extraordinary sensitivity can be achieved [152].
To date, all most all biochemical methods for acute myocardial
infarction (AMI) diagnosis are based on Enzyme-Linked Immu-
noSorbent Assay (ELISA). ELISA is an antibody (Ab) -based tech-
nique using a surface immobilized Ab1 and an enzyme-linked Ab2
to sandwich the target, converting each target into an Ab1/target/
Ab2 sandwich for sensitive enzymatic detection [153,154]. Al-
though ELISA been renowned as one of the fastest growing tech-
nologies used in clinical diagnostics for detecting specific proteins
associated with disease; however, for clinical diagnoses of AMI,
cardiac markers need additional chemicals. Moreover, compact test-
strips are able to give qualitative, but not quantitative information
on cardiac biomarkers. In addition, compared with commercially
available ELISA systems, nanobiosensor (electrochemical immu-
nosensor) is cheaper [155].
Suprun, et al. developed an electrochemical nanosensor with
immobilized anti-myoglobin (Mb) [146]. The fabricated nanobio-
sensor was quantified Mb (biomarker) for acute myocardial infarc-
tion (AMI) diagnosis. The detection system based on electron trans-
fer between Fe (III) -heme and electrode surface modified with gold
nanoparticles/didodecyldimethylammonium bromide (DDAB/Au)
and antibodies. The method proposed does not require signal en-
hancement or amplification; nor does it require labeled secondary
antibodies. Immunosensor has a detection limit of 10 ng/ml (0.56
nM) and a broad range of working concentrations (10-1780 ng/ml;
0.56-100 nM). The whole procedure takes 30 min and can be used
for express diagnosis of acute myocardial infarction [155].
5.3.1. Biomedical or Biological Micro-Electro-Mechanical
Systems (BioMEMS)
In recent years, the biological and biomedical applications of
micro- and nanotechnology (commonly referred to as Biomedical
or Biological Micro-Electro-Mechanical Systems [BioMEMS])
have become increasingly prevalent and have found widespread use
in a wide variety of applications such as diagnostics, therapeutics,
and tissue engineering [156,157]. In general, BioMEMS can be
defined as ‘‘devices or systems, constructed using techniques in-
spired from micro/nano-scale fabrication, that are used for process-
ing, delivery, manipulation, analysis, or construction of biological
and chemical entities’’[157,158]. These devices and systems en-
compass all interfaces of the life sciences and biomedical disci-
plines with micro- and nanoscale systems. Areas of research and
applications in BioMEMS range from diagnostics, such as DNA
and protein micro-arrays, to novel materials for Bio-MEMS, micro-
fluidics, tissue engineering, surface modification, implantable
BioMEMS, systems for drug delivery, etc. [156-160]. The recent
progress in BioMEMS and nanosensors crates very effective tools
for the early detection and diagnosis of CVDs. For example, the
nanowire integrated potassium and dopamine sensors are optimized
for the monitoring and diagnosis of acute myocardial infarction
[161].
4488 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
5.4. Controlled Drug Delivery or Targeted Therapeutic
Research in the areas of drug delivery has endorsed enormous
progress in recent years due to their unlimited potential to improve
human health. The limitations of current drug delivery systems
include suboptimal bioavailability, limited effective targeting and
potential cytotoxicity. Meanwhile, the development of nanotech-
nology provides opportunities to synthesize with controlled compo-
sition, shape, size and morphology, characterize, manipulate the
matter systematically at the nanometer scale [107]. In particular,
they can enhance the therapeutic activity by prolonging drug half-
life, improving the solubility of hydrophobic drugs and releasing
drugs at a sustained rate. Moreover, their surface properties can be
manipulated to enhance solubility, immunocompatibility and cellu-
lar uptake. In addition, nanoscale particles can passively accumu-
late in specific tissues (e.g., tumors) through the enhanced perme-
ability and retention (EPR) effect [162].
The promising and versatile nano-scale drug-delivery systems
include nanoparticles, nanospheres, nanocapsules, nanotubes, nano-
gels and colloidal carriers such as liposomes or dendrimers. They
can be used to deliver small-molecule drugs, growth factors, en-
zymes and/or biomacromolecules, such as peptides, proteins, plas-
mid DNA and synthetic oligodeoxynucleotides which provide a
sustained therapeutic stimulus at the injured tissue [107, 163].
5.4.1. Nanopaticles (NPs) Based Controlled Drug Delivery
The NPs have been exploited for both diagnostic and therapeu-
tic purposes. They have been used as a controlled drug delivery
vehicle for a variety of diseases; however, in the cardiac field, most
NP work has focused on detection of myocardial infarction [164].
The ideal size of NPs used as drug delivery systems ranges from 10
to 100 nm [164]. Further, these NPs based control drug release, can
targeting and increase the effectiveness or bioavailability of many
diagnostic or therapeutic agents. Among the materials most com-
monly used for cardiovascular drug-delivery systems are the NPs
made of synthetic or natural polymers, such as liposomes, dextrans,
poly (lactic-co-glycolic acid) (PLGA), polyaccrylates, as well as
metal or metal oxide nanoparticles (e.g., gold, silver, SPION), and
quantum dots. Several of the commonly tested drug-carrier systems
are briefly outlined below.
Among the NPss based drug-delivery systems, liposomes have
relatively low toxicity and a good therapeutic index. Liposomes are
composed of a lipid bilayer consisting of amphipathic phospholip-
ids (primarily phosphatidylcholine) that enclose an interior aqueous
space [165]. The head groups of phospholipids are usually func-
tionalized with polymerizable moieties to improve their stability.
Liposome mediated site-directed drug delivery of plasminogen
activators have been explored by various research groups for CVDs
treatments [166,167]. For example, the activation of platelets is
mediated by the binding of fibrinogen through RGD (Arg-Gly-Asp)
motif and therefore, it has been reported that RGD-peptides conju-
gated liposomes have an affinity towards activated platelets and
may be useful for the targeted delivery of thrombolytic agents
[168,169]. However, the liposomes, originally used as transfection
reagents for siRNA or gene delivery, can be functionalized with
ligands (e.g antibodies or polymers) offers low immunogenicity,
which is expected to enable safe and repeated administration [170].
Poly (lactic-co-glycolic acid) (PLGA), is a common and widely
used polymer due to its biocompatibility and biodegradability.
PLGA have approved by the U.S. Food and Drug Administration
(FDA) and the European Medicine Agency (EMA) for parenteral
administration of a drug carrier system [171]. The PLGA can easily
metabolize and hence eliminated from the body due to smooth deg-
radation of PLGA into their constituent products (lactic acid and
glycolic acid). Thus, expected systemic toxicity associated with
PLGA administration is low and safe [172]. However, Chang et al.
[173] have recently developed the insulin like growth factor 1 (IGF-
1) complexes with PLGA nanoparticles, and injected into the
ischemic myocardium, has shown a significant decrease in myocar-
dial apoptosis by inducing (protein kinase B) Akt phosphorylation.
Moreover, it is suggested that, as compared with larger particles,
the smallest (60 nm) sized PLGA-IGF-1 NPs carried more IGF-1
and induced more Akt phoshorylation in cultured cardiomyocytes.
Kona et al. [174] developed targeted NPs as a drug carrier system
that mimics platelets binding to the injured vessel wall under
physiological fluid flow (shear stress) conditions. Glycoprotein Ib-
alpha (GPIb-) of platelets was chosen as the targeting ligand and
conjugated to dexamethasone (drug) -loaded biodegradable poly-
(D, L lactic- co-glycolic acid) (PLGA) nanoparticles. The NPs were
formulated using a standard emulsion method. The results demon-
strate that conjugated NPs (GPIb-PLGA) have increased particle
adhesion onto target surfaces (P-selectin) of damaged endothelial
cells (ECs). In addition, under shear stress condition, cellular up-
take of these NPs by activated endothelial cells found increased.
Therefore, drug-loaded, conjugated NPs (GPIb-PLGA) could be
used as a targeted and controlled drug delivery system to the site of
vascular injury for treatment of CVDs.
They reported that vascular carrier may accumulate in the
thrombus and decrease the systemic degradation of the drug as well.
For optimal drug delivery, drug should be localized at the site of
thrombus and should avoid its non-specific uptake of unwanted
tissue. Thus, a well designed drug delivery system; surface modi-
fied with targeting moiety for targeted delivery of thrombolytic
agents to the site of thrombus may provide an effective alternative
[175]. Platelets play an important role in various thromboembolic
diseases. Under normal physiological conditions, platelets circulate
independently inside the blood vessels without interacting with
other factors or the vascular endothelium. However, at the action of
endothelial damage, blood platelets found contact with the subendo-
thelial extracellular matrix, perform a series of reactions and leads
to the formation of a platelets-rich hemostatic plug [176].
5.5. Tissue Engineered Biomaterials for Treatment of CVDs
The present treatments for the loss or failure of cardiovascular
functions, including organ transplantation, mechanical devices,
surgical reconstruction, or the administration of metabolic products
are although have been routinely used; these treatments are under
constraints and complications [177]. Tissue engineering is an alter-
native method for the treatment of CVDs (Fig. 3). Tissue engineer-
ing seeks to restore the function of diseased or damaged tissues
through the use of cells and biomaterial scaffolds [178]. In recent
years, progress has been made in the engineering the various com-
ponents of cardiovascular system, such as heart valves, blood ves-
sels, and cardiac muscle. Moreover, many pivotal studies are con-
ducted for the widespread applications of tissue engineered therapy
for CVDs. In engineered skeletal and myocardial tissue constructs,
designed scaffolds should match to the native tissue mechanical
properties as well as to enhance cell alignment [179]. The next
generation of functional tissue replacements such as skeletal and
myocardial tissue constructs for the treatment CVDs will require
advanced material strategies to achieve many of the important re-
quirements for long-term success. Therefore, viewing the rapid
evolution in the field of tissue engineering, it is essential to consider
the use of advanced materials in light of the emerging role of genet-
ics, growth factors, bioreactors, and other technologies [180].
Cardiovascular tissue engineering has the potential to improve
the ability to treat CVDs and the single greatest cause of mortality
in the United States. Recently, a significant step could be taken
towards the improvement in the type of heart valves used to replace
diseased and damaged heart valves. Significant progress of the
tissue engineering has been obtained in recent years. However, the
major limitations in tissue engineering are the cultivation and for-
mation of complex tissue constructs to keep viable in vitro as well
as in vivo during implantation [181]. Moreover, replacement struc-
tures manufactured from autologous cells and bioabsorbable poly-
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4489
mer scaffolds using engineering techniques to contain living cells,
these structures have growth potential, imparts less infection and
calcification, and decrease incidence of thrmboembolic complica-
tions [182]. One of the first materials used for tissue engineering of
the allogenic heart valve was biodegradable and biocompatible
polymers of polylactic acid, polyglycolic acid (PGA) and their co-
polymer polylactic-co-glycolic acid (PLGA) or of poly (-
caprolactone) (PCL) [180-182].
5.5.1. Copolymer Polylactic-Co-Glycolic Acid (PLGA)
Hu et al. [181] fabricated a kind of poly (lactide-co-glycolide-
70/30) (PLGA-70/30) microtubular orientation-structured blood
vessel mimicking natural structure by an improved thermal-induced
phase separation (TIPS) technique. By adjusting various parameters
of TIPS techniques such as temperature, concentration of polymer
solution,and inner-and outer-diameter of the polyethylene (PE)
mould (for manufacturing the orientation-structured blood vessel
scaffolds), various microtubular orientations-structured blood ves-
sels scaffolds with different wall thickness was obtained. The cell
affinity of the scaffolds was evaluated in vitro by using A10 cells as
model cells. The results showed that the A10 cells grew (seeded
and migrated) in the vessel scaffolds which were modified by am-
monia plasma treatment and then anchored with collagen. The cells
were found along the direction of the microtubules and showed
high viability and rapid proliferation. With this connection, Ma et
al. fabricated a type of novel scaffolds to better engineered blood
vessels of small-diameter from biodegradable poly (L-lactic acid)
(PPLA) by means of thermally induced phase separation (TIPS)
techniques [183]. By applying the differences in thermal conductiv-
ities of the mould materials and using benzene as the solvent scaf-
folds with oriented gradient microtubular structures in the axial or
radial direction can be prepared. The structural properties of such
scaffolds can be conventionally adjusted by varying the solvent
ratio, phase-separation temperature, and polymer concentration to
mimic the nanofibrous features of an extracellular matrix. These
scaffolds were fabricated for the tissue engineering of small-
diameter blood vessels by using their advantageous structural prop-
erties to facilitate blood-vessel regeneration. Han et al. fabricated a
novel biomimetic scaffolds for application in vascular tissue engi-
neering from co-electrospinning tertiary blends of poly (lactide-co-
glycolide) (PLGA), gelatine, and elastin (PGE). By varying the
ratios of PLGA and gelatin, fine-tune fibers, swelling (on hydra-
tion) and enhanced mechanical properties of the scaffold was ob-
tained [184]. Moreover, the effect of the varying ratios of PLGA
and gelatin on vascular cell morphology and growth on and pene-
tration into the scaffolds was investigated. Further, the electrospun
PGE scaffolds supported the attachment and metabolization of hu-
man endothelial cells (ECs) and bovine aortic smooth muscle cells
(SMCs) and their organotypic distribution on and within the scaf-
folds. Taken together, the results indicated that the PGE scaffolds
were potential in vascular tissue engineering. Nguyen et al. devel-
oped multilayered scaffolds composed of polycaprolactone (PCL) -
gelatin/poly (lactic-co-glycolic acid) (PLGA)-gelatin/PLGA-
chitosan with different diameters using the double-ejection elcetro-
spinning system [185]. The effects of the cross-linking process on
the mechanical behaviors, microstructure, and biocompatibility of
the fibers were investigated. The cross-linked elctrospun scaffolds
satisfied the three requirements for artificial blood vessels (ABVs),
such as resistance to intermediate pressure, flex ibility, and the abil-
ity to promote cell growth and proliferation. Moreover, the biocom-
patibility of the cross-linked ABV scaffolds were examined using
the MTT assay and by evaluating cell attachment and cell prolifera-
tion. In addition, the multilayered ABVs imparted high tensile
strength (2.3MPa of stress and 100% of strain) and liquid strength
(340 mmHg), which are essential for implantation. Taken together,
the use of an elctrospinning array to form multicomponent nanofi-
brous membranes will lead to the creation of novel scaffolds and
holds great promise for eventual use in ABVs.
5.5.2. Poly (-Caprolactone) (PCL)
Cardiovascular diseases (CVDs) are the leading cause of death
in the United States with many patients requiring coronary artery
bypass grafting. The recent years autografts such as using intimal
mammary artery or saphenous vein, could be replaced by creating a
synthetic grafts for eliminating inconvenient procedures. In addi-
tion, large diameter grafts have long been established with materials
such as teflon and dacron, however, these materials have not proved
successful in small diameter (< 6 mm) grafts [186].
Fig. (3). A Basic of tissue engineering (TE) construct for CVDs. For the construction of 3D cardiovascular tissue engineered grafts, nanofiberous scaffolds
were seeded with vascular and cardiac muscle cells. Further, the seeded scaffolds are functioning in addition of growth factors or signalling molecules.
Tissue Engineering
Construct for CVDs
Nanofibers for TE Scaffold
Signalling Molecules or Growth Factors
Stem Cell Differentiation of Stem Cell
Vascular Cells
Cardiac Muscle Cells
4490 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
Gupta et al. have hypothesized that polymeric biomaterials
scaffolds with distinct chemical and mechanical properties could be
employed to enhance the differentiation of embryonic stem cells
(ESCs) to cardiomyocytes as a potential patch for cardiac repair
[187]. A combinatorial polymer was prepared by copolymerizing
three distinct subunits at varying molar ratios to tune the physical
properties of the resulting polymer such as, hydrophilic polyethyl-
ene glycol (PEG), hydrophobic poly (-caprolactone) (PCL), and
negatively-charged, carboxylated PCL (CPCL). Interestingly, Mur-
ine ESCs on the most compliant substrates, 4%PEG-86%PCL-
10%CPCL (electrospun polymeric scaffolds), exhibited the highest
myosin heavy chain (-MHC) expression as well as intracellular
Ca2+ signalling dynamics (depolarization and repolarization path-
way) and optimally facilitated the differentiation of ESCs into func-
tional cardiomyocytes. These results are promising for the treatment
of cardiac ischemia, where the ensuing myocardial hypoxia and
fibrosis may be treated through the delivery of a tissue-engineered
myocardial patch. Seyednejad et al. [188] fabricated nanofibrous
scaffolds based on blends of a hydroxyl functionalized polyster
(poly (hydroxymethylglycolide-co--caprolactone), pHMGCL) and
poly (-caprolactone) (PCL) by means of a coaxial electrospinning
technique. The scaffolds were loaded with bovine serum albumin
(BSA) as a protein stabilizer and vascular endothelial growth factor
(VEGF) as a potent angiogenic factor for tissue engineering appli-
cations. Moreover, the effect of releasing protein (VEGF) on the
attachment and proliferation of endothelial cells was investigated.
The fabricated pHMGCL scaffolds showed an enhanced protein
release (VEGF) as well as increased hydrolysis rate as compared to
PCL scaffolds. The incorporated proteins preserved in pHMGCL
scaffolds showed its biological activity and higher numbers of ad-
hering cells. Thus, these bioactive scaffolds based on blends of
pHMGCL/PCL loaded with VEGF can be considered as potential
candidates for tissue engineering applications. Lee CHY. synthe-
sized a novel tri-layered tissue engineered blood vessels contain
microchannels from biodegradable polymer (polycaprolactone) by
electrospinning and laser ablation techniques [189]. The tri-layered
blood vessels to mimic native arteries that have an endothelium to
protect thrombosis in the inner layer, aligned, smooth muscle cells
in the middle to control constriction and vasodilation, and a me-
chanically robust outer layer. The mechanical properties such as
tensile, fatigue, brust pressue, and suture retention strength were
investigated. In addition, the biological interactions between the co-
culture of endothelial and smooth muscle cells with elctrospun PCL
scaffolds were evaluated. The results concluded that the elctrospun
tri-layers provided an adequate mechanical strength and the micro-
channels are able to contain the smooth muscle cells, and that cells
are able to adhere to PCL fibers. Han et al. [190] developed elc-
trospun-multilayered vascular scaffold in 1.5 mm diameter with
sufficient mechanical properties of poly (ethylene glycol) -b-poly
(lactide-co- -caprolactone) (PELCL), poly (ethylene glycol)
(PLGA), poly (-caprolactone) (PCL) and gelatine. The combina-
tion of PELCL, PLGA and PCL in three layers possessed 5.2 ± 0.7
MPa tensile strength, 146.7 ± 0.6% elongation and 6534 ± 926 mm
Hg burst pressure, higher than single component and comparable to
natural vessels. Spatio-temporal releases of growth factors, such as
vascular endothelial growth factor (VEGF) and platelet-derived
growth factor-bb (PDGF) and mechanical stability were controlled
by inner (PELCL), middle (PLGA) and outer (PCL) layers in that
order. However, gelatin significantly increased vascular endothelial
cell (VECs) adhesion on lumen and promoted VSMCs infiltration
from the outer layer in the middle layer. Cell activities indicated
dual release of growth factors (VEGF and PDGF). The improved
vascular grafts with dual-loading growth factors could maintain
potency in rabbit left common carotid artery for 8 weeks, compared
to other sample loading one kind of growth factor or without load-
ing any growth factor. Therefore, it is concluded that the specially
prepared vascular graft could benefit the blood vessel reconstruc-
tion.
Wang et al. fabricated a PCL tubular freeze-dried scaffold for
small diameter blood vessel replacements. The PCL scaffold was
prepared by dissolving PCL in acetic acid (15wt %) solution [191].
Further, the PCL scaffold was reinforced by embedding a tubular
fabric that was knitted from polyethylene terepthalate (PET) yarns
within the freeze-dried composite structure. The mechanical proper-
ties of reinforced scaffolds such as tensile strength, initial modulus,
radial compliance, compression recovery, and suture retention
force, were significantly improved compared to those of the unrein-
forced sample. Moreover, the reinforced composite structure is a
candidate for use as a tissue engineered scaffold for a future small
diameter vascular prosthesis. Furthermore, Wang et al. fabricated
vascular grafts from mesoporous elctrospun polycaprolactone
(PCL) scaffolds with thicker fibers (5-6 m) and large pores (~30
m) for macrophage polarization and arterial regeneration [192].
Further, demonstrated that thicker-fiber elctospun PCL grafts with
large pore sizes significantly enhanced cell infiltration, migration,
and vascularisation. In addition, the thicker fiber pores also stimu-
late the macrophage polarization into M2 phenotype (in vitro),
which subsequently mediated the regeneration process of vascular
grafts (neo-arteries in vivo) in comparison with the regular thinner-
fiber PCL grafts. In vitro culture showed that macrophages cultured
on thicker-fiber scaffolds tended to polarize into the immunomodu-
latory and tissue remodelling (M2) phenotype, whereas those cul-
tured on thinner-fiber scaffolds expressed pro-inflammatory (M1)
phenotype. In vivo implantation by replacing rat abdominal aorta
was performed and followed up for 7, 14, 28, and 100d. The results
demonstrated that the macroporous grafts significantly enhanced
cell infiltration and extracellular matrix (ECM) secretion. All grafts
showed satisfactory potency for up to 100 days. At day 100, the
endothelium coverage was complete, and the regenerated smooth
muscle layer was correctly organized with abundant ECM similar to
those in the native arteries. Moreover, the regerenated arteries dem-
onstrated contractile response to adrenaline and acetylcholine-
induced relaxation. In addition, cellularization process revealed that
the thicker-fiber scaffolds induced a large number of M2 macro-
phages to infiltration and vascularization into the graft wall. The
findings demonstrated that the combined biomaterial-immuno-
modulatory approach of thicker-fiber elctrospun PCL vascular
grafts should help with better design next generation of vascular
grafts and suggesting a promising candidate for future in vivo
evaluation. Yao et al. [193] developed a hybrid small-diameter
vascular graft (inner diameter of 1.5 mm) from synthetic polymer
poly (-caprolactone) (PCL) and natural polymer chitosan (CS) by
the co-elctrospinning technique. The prepared PCL/CS vascular
grafts had a tri-layer structure with a mass ratio varying from 5/4,
5/2 to 5/1 (w/w) for inner, middle and outer layers, respectively.
The vascular graft was further functionalized by immobilization of
heparin. The release heparin was monitored, and the effect of hepa-
rin release on the hemocompatibility, vascular cell proliferation and
inhibition of thrombus formation was investigated in vitro and in
vivo. The in vitro cell proliferation assay showed that heparin can
promote the growth of human umbilical vein endothelial cells
(HUVECs), while moderately inhibiting the proliferation of vascu-
lar smooth muscle cells (VMCs), a principal factor for neointimal
hyperplasia. Implantation in rat abdominal aorta for 1 month dem-
onstrated the heparin functionalized PCL/CS grafts sustained re-
lease of heparin with optimal anti-thrombogenic effect by reducing
thrombus formation. Furthermore, functionalized graft provided
better endothelialization and potency in comparison with the con-
trol group. In conclusion, heparin functionalized PCL/CS grafts
provided a facile and useful technique for the development of hea-
parinized medical devices, including vascular grafts. Wang et al.
[194] prepared a hybrid scaffold that consists of synthetic PCL
fibers and native gelatin (Gel) fibers by co-elctrospinning tech-
nique. The PCL provides optimal mechanical strength, while gela-
tin was heparinised in order to deliver VEGF in a controlled manner
which is monitored by in vtro releasing test. The mechanical prop-
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4491
erties and surface hydrophilicity was investigated. The effect of
releasing VEGF from the heparinised PCL/Gel scaffolds on im-
proving vascularisation has been investigated by both in vitro cell
experiment and in vivo subcutaneous implantation. The mechanical
properties and surface hydrophilicity was found satisfied as require
to the tissue engineering scaffolds. In vitro cell assay indicated that
VEGF release significantly enhanced the proliferation of endothe-
lial cells. More importantly, in vivo subcutaneous implantation
showed that the neovascularisation significantly improved in
PCl/Gel scaffolds compared with PCL counterpart due to sustained
release of VEGF. Thus, taken together the above properties, the
developed heparinised PCL/Gel scaffolds are a promising candidate
for the regeneration of complex tissues with sufficient vascularioza-
tion.
5.5.3. Poly (Ethylene Glycol) (PEG)
Leslie-Barbick et al. prepared a microvasularization of tissue
engineered constructs by using a VEGF (vascular endothelial
gro wth factor) -mimicking peptide, QK (Gln-Lys), covalently
bound to a poly (ethylene glycol) (PEG) hydrogel matrix [195]. The
PEGyalation of peptides (QK) increased its bioactivity and solubil-
ity, as evidenced by endothelial cell proliferation assay. In addition,
PEGyaltion of peptides showed the equal or superior ability to
promote angiogenesis in vitro within 3-D collagenase hydrogels
and on the surface of hydrogels, compared to PEG-VEGF hydro-
gels or only RGD (Arg-Gly-Asp) peptide sequences. Thus, PEG-
QK provided an alternative to the use of growth factor proteins in
angiogenic signalling. Zhu et al. [196] reported on the synthesis of
extra cellular matrix (ECM) -mimetic poly (ethylene glycol) (PEG)
hydrogels for inducing endothelial cell (EC) adhesion and capillary-
like network formation. A collagen type I-derived peptide (GIA)
containing PEGDA (PEGDA-GIA) was synthesized with the colla-
genase-sensitive GIA sequence attached in the middle of the
PEGDA chain, which was then copolymerized with RGD capped-
PEG monoacrylate (RGD-PEGMA) to form biomimetic hydrogels.
In addition, biomimetic RGD-PEGDA/GIA-PEGDA hydrogels,
showed an induced capillary like organization, on human umbilical
vein ECs (HUVECs) seeded hydrogel surface, compared to
RGD/PEGDA and GIA/PEGDA hydrogels. These results indicated
that the both cell adhesion and biodegradability of scaffolds paly an
important role in formation of capillary-like networks.
5.5.4. Polyurethane
There are few synthetic elastomeric biomaterials that simulta-
neously provide the required biological conditions and translate
biomechanical stimuli to vascular smooth muscle cells (VSMCs)
[197]. Polyurethanes are the class of synthetic polymers or elastom-
ers that have been performed various vascular tissue engineering
applications, such as ability to control high degree of different me-
chanical properties, tailored biochemical signalling, and specific
cell and material interactions, which ultimately influences extracel-
lular matrix (ECM) synthesis and tissue regeneration [198].
Sharifpoor et al. [199] developed a customized bioreactor used to
investigate the effects of uniaxial cyclic mechanical strain (CMS)
on human coronary artery smooth muscle cells (hCASMCs). The
cells (hCASMCs) were cultured in a porous degradable po-
lar/hydrophobic/ionic (D-PHI) polyurethane scaffold and its cell
viability as well as growth has been assessed. In addition, distribu-
tion, proliferation and protein expression of cells (hCASMCs) in
the scaffolds were then analyzed and compared to those grown
under control conditions. The resulted CMS-scaffolds showed a
greater DNA mass, more cell area coverage, and a better distribu-
tion of cells deeper within the scaffold construct. Moreover, CMS-
scaffolds provided enhanced tensile mechanical properties and
showed improved expression of contractile proteins (actin, myosin
and calponin), suggesting that hCASMCs retained the contractile
behavior on these CMS-scaffolds biomaterials. Du et al. [200] de-
veloped a 3D gradient heparinised nanofibrous scaffolds from ver-
tical graded elctrospun chitosan/poly -caprolactone (CS/PCL)
aiding endothelial cells lined on the lumen of blood vessel to pre-
vent thrombosis. Moreover, scaffolds were designed such a way
that, modify the surface properties of the scaffolds using heparin,
since it has been shown that heparinization and immobilization can
control the vascular endothelial growth factor (VEGF) delivery by
potentially increasing endothelial cells bioaffinity, proliferation and
anticoagulation properties. Furthermore, the quantity of heparinised
chitosan nanofibers increased gradually from the tunica adventitia
to the lumen surfaces in the gradient CS/PCL wall of tissue engi-
neered vessel. More heparin reacted to chitosan nanofibers in gradi-
ent CS/PCL than in uniform CS/PCL nonofibrous scaffolds. The
adhesion and proliferation of human umbilical vein endothelial
cells (HUVECs) were increased on the gradient CS/PCL scaffolds.
In addition, HUVECs grew and formed an entire monolayer on the
top side of the gradient CS/PCL scaffold. Taken together, the use of
vertical gradient heparinozed CS/PCL nanofibrous scaffolds could
provide an approach to create small-diameter blood vessel grafts
with similar natural blood vessels.
Although polyurethanes very often suffer from poor in endo-
thelization, are freqently used in the cardiovascular field due to
their tunable physiochemical properties and acceptable hemocoma-
patibility. For which, polyurethanes are synthesized as degradable
segmented products with help of amino acids as chain extenders.
Chan-Chan et al. [201] synthesized a cost-effective and straight-
forward method to enhance endothelial cell adhesion to the degrad-
able segmented poly (urea) urethanes (SPUUs) containing amino
acids (either L-arginine, glycine or L-aspartic acid) as chain ex-
tenders. These amino acids are selected on the basis of their differ-
ent pH behavior and their ability to form charged species since it
has been shown that positively charged surfaces can promote cell
adhesion while a slightly hydrophilic surface can enhance prolifera-
tion of cells. The alkaline L-arginine, neutral glycine and acidic L-
aspartic acid were incorporated separately into the polyurethane
backbone to provide both bulk and surface properties of the poly-
mer. All polymers showed a little mass loss (slow degradation) in
PBS (pH 7.4) but a higher mass loss (accelerated degradation)
showed under alkaline, acidic and oxidative media. The polyure-
thanes with L-aspartic acids exhibited poor mechanical properties.
Moreover, MTT tests on polyurethanes with L-arginine showed no
adverse effect on the metabolism of human umbilical vein endothe-
lial cells (HUVECs). However, polyurethanes with L-arginine
showed an enhanced higher level of HUVECs adhesion, spreading
and viability after 7 days compared to commonly used Tecoflex
polyurethane as a control. Taken together, along with a slow degra-
dation rate of polyurethanes containing L-arginine would be a po-
tential candidate for cardiovascular applications and angiogenesis.
Jing et al. [202] fabricated a thermoplastic polyurethane (TPU)
/grapheme oxide (GO) composite membrane and tubular scaffolds
(inner diameter of 3.18 mm) via elctrospinning at different GO
contents (0.5%, 1% and 2%) as potential candidates for small di-
ameter vascular grafts. In addition, the structure, properties and cell
response on the TPU/GO elctrospun scaffolds were investigated.
For investigation of cell response, mouse fibroblasts (3T3) and
human umbilical vein endothelial cells (HUVECs) were tested on
the TPU/GO elctrospun fibers. Further, suture retention assets, cy-
clic tensile tests, and burst pressure tests were conducted on
TPU/GO scaffolds to verify their ability to be used in vascular scaf-
fold applications. In terms of mechanical and surface properties, the
tensile strength, Young’s modulus, and hydrophobicity of scaffolds
(on plasma treatment) were found to increase with an increase of
GO contents. It was found that cell viability for both types of cells,
fibroblast (3T3) proliferation, and HUVECs attachment were the
highest at a 0.5 wt. % GO loading whereas oxygen plasma treat-
ment also enhanced HUVECs viability and attachment signifi-
cantly. Further, the suture retention strength and burst pressure of
tubular TPU/GO scaffolds containing 0.5 wt. % GO was found to
resemble with the native blood vessel and also endothelial cells
were able to attach to the inner surface of the tubular scaffolds. The
4492 Current Pharmaceutical Design, 2015, Vol. 21, No. 30 Behera et al.
platelet adhesion tests indicated that vascular scaffolds containin g
0.5 wt. % GO had low platelet adhesion and activation, and is un-
likely to cause thrombosis on the scaffolds. Therefore, the electros-
pun TPU/GO tubular scaffolds have the potential to be used in vas-
cular tissue engineering.
5.5.5. Silk
Zhu et al. [203] designed and fabricated porous 3-D silk fibroin
(SF) scaffolds and tubular scaffolds by modifying the freeze-drying
method which could be used as potential vascular grafts. The de-
veloped SF scaffolds provided the remarkable mechanical property,
excellent biocompatibility and biodegradability, and low immuno-
genicity. Furthermore, the anticoagulant activity of the heparin-
loaded SF scaffolds was investigated. In vitro assays were per-
formed to assess the effects of heparin-loaded SF scaffolds on hu-
man smooth muscle cell (hSMC) proliferation and infiltration. In
addition, the impact of the SF scaffolds on the tissue ingrowth and
neovascularisation were also examined in vivo by subcutaneous
implantation in rats. The incorporation of heparin during fabrication
possessed significant anticoagulant property and released in a sus-
tain manner for approximately 7 days. The heaparin-loaded scaf-
folds, showed inhibition of hSMCs proliferation within scaffold (in
vitro) and while significantly promoted hemocompatibility and
neovascularisation (in vivo) in subcutaneous implantation in rats.
Thus, heparin-loaded SF scaffolds considered as potential vascular
grafts.
6. DISCUSSION
Nanotechnology and nanomedicine have recently emerged as
alternative and promising therapeutic method for the treatment of
CVDs and related diseases. The potential technology utilizes
nanoscale dimension materials and bridges the gap between mo-
lecular and cellular interactions, and has the potential to revolution-
ize medicine [83]. In addition, as compared to traditional medicine,
nanomedicine offers early diagnosis, to treat as effectively as possi-
ble with minimal side effects and an improved clinical result [204].
Various nanotechnology applications are being studied for the
treatment of atherosclerosis and restenosis, and related CVDs in-
cluding nanocarriers for drug delivery. The major nanocarrier
classes explored as therapeutic and theranostic (i.e., particles inte-
grating diagnostic imaging and therapeutic components). Nanopati-
cles (NPs) such as SPIONs have been used as a prolonged anti-
angiogenesis therapy and MRI imaging with targeted thrombolysis
[205]. There is also the reversed side of interaction of NPs with the
walls of blood vessel. The vascular endothelium could be an obsta-
cle and undesirable target for NPs to be delivered to other organs
[92]. In this regard, CVDs may affect the transport of NPs across
vessel walls, organelle-targeted delivery of NPs, and other effects
of NPs on vessel cells. These factors should be taken into account
in future nanomedical research.
Gene delivery and therapy is the most notable therapy, hold
great promise as treatment and prevention methods for CVDs [206].
However, the systemic administration of these therapeutics is af-
fected by several barriers such as uptake by the reticuloendothelial
system, enzymatic degradation, kidney filtration, and limited intra-
cellular entry. Therefore, nanocarriers have been widely used to
overcome and best alternative to make therapeutics of CVDs be-
comes more efficient [206]. In addition, site-targeted drug delivery
holds promise in the treatment of vascular injury-associated throm-
botic and occlusive events caused by cardiovascular diseases (e.g.
atherosclerosis) or interventional procedure (e.g. angioplasty and
stenting). However, conventional techniques are expensive and
require experienced personnel for their use [95]. Thus, a novel car-
rier based targeted delivery of thrombolytic agents is a desirable
promising strategy for the thrombolytic agents is a desirable prom-
ising strategy for the treatment of thromboembolic diseases. How-
ever, the systemic side effects of these thrombolytic agents
(systemic fibrinogenolysis and bleeding) raise and impose unavoid-
able clinical difficulties. The side effects of therapeutic agents
comprise proteolytic components of the blood clotting cascade, and
thus their thrombolytic abilities are also responsible for their capac-
ity to disrupt haemostasis systemically. To reduce the incidence of
the systemic side effects thrombolytic agents could specifically
delivered targeted to the thrombus sites in vivo, or particular dos-
ages which are required and used for therapeutically effective ef-
fects of drugs at the thrombus site [118].
On the other side, quantum dots (QDs) contain toxic compo-
nents (such as Cd). The coating/ functionalization with QDs have
been used with nontoxic materials such as organic mole-
cules/polymers (e.g. PEG) or inorganic layers (e.g. ZnS and silica)
to reduce the levels of toxicity. Therefore, several groups of re-
searchers have been studied the water soluble QDs encapsulated by
amphiphilic polymers (with PEG), claimed very low toxicity to
cells [207-209]. In recent years, tissue-engineering (TE) scaffolds
have been fabricated by emphasized the control over cell behaviors.
The tissue formation can be functionalized by tissue engineered
scaffolds that closely mimics the natural extracellular matrix
(ECM). By understanding the behaviors of natural ECM, research-
ers have been developing/ constructed nanofibrous scaffolds/nano-
composites through electrospinning or self-assembly techniques
[210].
Beside all these facts, nanotechnology based formulated drugs
has made a significant impact on the treatment of CVD. The field of
cardiovascular therapeutic and theranostic holds tremendous prom-
ise and excitement for basic and clinical scientists to work together
to explore the possibilities of nanoscale technologies for the treat-
ment of CVDs.
CONCLUSION
In developed and developing countries, CVDs symbolize an
enormous burden on the healthcare system and economy because
they are the leading cause of morbidity and mortality [138]. The
most challenging goal in the field of cardiovascular tissue engineer-
ing is the creation/ regeneration of an engineered tissue for re-
placement or transplant. Recent advances in cell scaffolds provide a
platform for delivery of bioactive molecules as well as a physical
environment to allow for cell attachment thus preventing cells from
being carried away. A variety of materials have been used as cell
scaffolds including synthetic and natural polymers and hydrogels,
native extracellular matrix (ECM) proteins, and processed native
ECM following myocardial infarction towards cardiovascular tissue
regeneration [93]. Moreover, in recent years, more advances in
methods of stem cell isolation, culture in bioreactors, and the syn-
thesis of bioactive materials promise to create engineered tissue ex
vivo. Furthermore, new modalities are perceived that explore ways
to induce cardiovascular tissue regeneration after injury.
The rapid evolution of nanotechnology, which connects the gap
between interactions on the nanoscale and macroscopic levels, one
of the major promising players in the development of the detection
and treatment of CVDs. Though still in the very early developmen-
tal stages, cardiovascular nanomedicine is likely to meet the high
demand for breakthrough innovation in the diagnosis and treatment
of CVDs. Nanomedicine enables the design of multi-functional
agents, which can simultaneously and precisely detect and treat
CVDs and related diseases. Thus, there remains a significant oppor-
tunity to develop new methods and techniques for the generation of
cardiovascular tissue engineering grafts, to promote therapeutic
strategies for CVDs treatments and to create fully functioning car-
diovascular tissues.
CONFLICT OF INTEREST
The authors confirm that this article content has no conflict of
interest.
Recent Advancement in the Treatment of Cardiovascular Diseases Current Pharmaceutical Design, 2015, Vol. 21, No. 30 4493
ACKNOWLEDGEMENTS
The authors acknowledge the financial support from Ministry of
Human Resource Development, Government of India, and TEQIP-
II programme funded by the World Bank.
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Received: April 14, 2015 Accepted: July 31, 2015
