Recent treatment modalities
for cardiovascular diseases
Introduction:
• The objective for the treatment of CVD is to reduce the amount of
hospitalizations that occur each year due to these diseases, to reduce mortality
from heart disease, and to reduce heart disease-related disability.
• Although current treatments in ischemic events are continually improving, the
main factor that determines the level of disability sustained by a cardiac event,
and even whether the patient survives, is usually time.
• The faster an individual receives percutaneous coronary intervention (PCI), the
better his or her outcome upon discharge
• Current strategies are designed to speed up the time from cardiac event onset to
receiving the appropriate medical intervention
• In addition, there are also many clinical trials currently underway that aim to
reduce or reverse the disease state and preemptively mitigate the level of
disability encountered by the patient following an ischemic event
• These procedures are also being evaluated for their ability to alter the
pathophysiology of hypertensive, inflammatory and myopathic diseases. 2
Stem cells
• Stem cells not only have the capability of self-renewal and proliferation, but
also have the ability to develop into multiple cell types that can ultimately
constitute viable tissue.
• Early on, proposed mechanisms of stem-cell therapy for CVD focused on
angiogenesis and myogenesis
• Since then, excitement for stem cell therapy has resulted in an abundance of
promising preclinical data and a rise in adult stem cell clinical trials
• Stem cells for CVD applications can be obtained from bone marrow-derived
cells, inducible pluripotent stem cells, resident cardiac stem cells,
mesenchymal or adipose tissue-derived stem cells, skeletal myoblasts, and
circulating stem cells
• These stem cells can be then directly injected into CVD site. A number of
studies have demonstrated the efficacy of stem cells for CVDs including
myocardial infarction and ischemic heart disease
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• However, due to the lack of understanding of basic principles, pathways and
transcription factor networks, as well as the complexity of the heart as an
organ, the use of stem cell therapy is not yet standard clinical practice
• Major challenges include optimal stem cell type, the optimum timing of stem
cell delivery, and the ideal application route.
• Mesenchymal stem cells (MSCs), a specific stem cell type, have shown
regenerative properties at disease sites including the secretion of trophic and
immunologic factors.
• However, MSCs have been difficult to control when grafting into the target
site, as their cytokine production is sporadic and can promote inflammatory
conditions.
• If researchers can develop methods to control the factors that enhance tissue
repair and reduce tissue damage, MSCs could prove to be therapeutically
beneficial.
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• Some researchers are studying exosomes, small bi-lipid membrane secreted
vesicles released by MSCs, as potential cell signaling methods to shift MSCs
into resolution, rather than an inflammatory state.
• In ischemic and coronary artery disease, these exosomes have been shown to
reduce ischemic and reperfusion injuries at the site of infarction in cardiac
tissue
• MSCs can also induce endothelial, cardiovascular and neovascular
differentiation in vitro and ex vivo
• The current therapies for CVDs predominantly act to prolong the onset or
progression of symptoms, and newer treatments are being designed to
reverse the disease process in individuals.
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• Cell-based therapies for patients suffering acute myocardial infarction (AMI)
or living with congestive heart failure have captured the attention of the
research community because current interventional strategies cannot
compensate for the irreversible loss of functional cardiomyocytes.
• At the forefront of therapy are mesenchymal and resident cardiac stem cells,
which are activated to differentiate into several different cell types
• These new developments refute previous notions that the heart is fully
differentiated and has limited restorative capabilities
• Although these cells have been shown to have a high degree of cell turnover
in vitro, their capabilities ex vivo or in vivo are less understood, though the
potential underlying mechanisms may be useful in several different cardiac
ailments
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Hypertensive disease
• Although there are no current strategies involving stem cell therapy in
vascular hypertensive disease, there have been some promising results using
stem cells to treat pulmonary hypertension (PH) in rodent models.
• MSCs can reduce hypoxia-induced damage and fibrosis, reverse injury to the
alveoli, and normalize lung function, and ultimately reverse moderate signs
of PH.
• PH commonly leads to right ventricle hypertrophy (RVH), which can
ultimately result in right-sided heart failure and systemic symptoms.
• In another rodent model, the PH and RVH decreased in response to
autologous MSC therapy and as a result normalized right ventricle ejection
fraction and lung weight
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Coronary artery disease
• Perhaps the largest target of stem-cell therapy is coronary artery disease
treatment post myocardial infarct.
• In randomized, double-blinded studies, it was found that MSCs have the
ability to improve left ventricular ejection fraction and reverse cardiac
remodeling
• These benefits are believed to be due to the successful replication and
differentiation of endogenous cardiac stem cells.
• In animal studies, injected MSCs induced differentiation and proliferation in
resident cardiac stem cells
• Other animal studies have shown that MSCs have the ability to engraft and
differentiate into cardiomyocytes and myocardial vasculature, which leads to
the secretion of paracrine and exosomal factors to promote healing
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• Current clinical trials aim to better elucidate the mechanism by which
transplanted MSCs elicit this action.
• For example, the functional integrated myocytes derived from MSCs are too
small in size to know if the healing effects are due to these cells, their
paracrine functions proteins or from their effect on other neighboring cells.
• Identification of these paracrine factors and administering them as
therapeutics will promote a reversal of remodeling
• Stem cells have not yet shown therapeutic potential in many of the other
classifications of CVD such as cardiomyopathies and arrhythmias.
• However, there are a growing number of cell models of these conditions,
which may aid in future understanding
• For example, dysregulation of calcium cycling is seen in hypertrophic
cardiomyocytes in hypertrophic myopathy.
• In addition, MSCs and pluripotent stem cells have been used for many years
as systems for studying dysrhythmias in a cardiac environment 10
Aptamers
• Aptamers are small RNA or DNA oligonucleotides that function as “chemical
antibodies” and exhibit a range of important diagnostic and therapeutic
applications
• Aptamers are developed completely in vitro through a system referred to as
“Systematic Evolution of Ligands by Exponential Enrichment” (SELEX), which
uses a series of target binding, washing and amplification steps to select DNA or
RNA oligonucleotides based on affinity for the target molecule
• Aptamers can be created that can bind with high specificity and affinity to a wide
array of biomedical targets including proteins and small molecules
• Aptamers possess several potential advantages over monoclonal antibodies, they
can be developed purely in vitro, there is low batch-to-batch variability, and
production and scale up is economical
• Aptamers lack the possible toxicities and immunogenicity of antibodies
• Aptamers do harbour several pertinent disadvantages. For one, due to their smaller
size, they are more quickly degraded than antibodies, and are also vulnerable to
endo- and exo-nucleases in vivo 11
• To combat these challenges, aptamers must be modified in vitro via chemical
additions, which slows excretion and protects them against nucleases, however, in
the process may also precipitate harmful side effects
• Aptamers have shown promise in a variety of cardiovascular therapeutic
applications, most prominently as antithrombotic and anticoagulants
• clinical trials are underway to assess aptamers against Von-Willebrand Factor
(vWF), thrombin and Factor IX.
• vWF-induced platelet activation plays a key role in multiple CVDs, including
CAD, acute coronary syndrome (ACS), AMI and peripheral vascular disease
• It is speculated that anti-vWF aptamers may prove useful in the treatment of these
conditions.
• Similarly, thrombin is a key regulator of intrinsic coagulation pathway and can
also activate platelets and inflammatory cytokines involved in plaque formation.
• Anti-thrombin aptamers are therefore being examined as possible therapeutic
tools.
• Aptamers that inhibit Factor IX, another key element of the intrinsic coagulation
cascade, are also undergoing clinical evaluation as possible antithrombotics 12
Exosomes
• Many cells in the cardiovascular system secrete nano-sized, lipid-bilayer
vesicles (40–100 nm) called exosomes which carry signaling molecules such
as protein, mRNA and miRNA are key players in intercellular
communication that mediate survival and homeostasis.
• Exosomes utilize a cell-cell communication method based upon release and
uptake of membrane-bound extracellular vesicles
• Exosomes first bind to target surface ligands inducing receptor-mediated
signal transduction, transfer surface receptors of EVs to target cell, and
finally deliver functional protein, lipids and RNAs within the EVs
• Exosomes serve as a promising tool for diagnostic and prognostic
biomarkers as well as efficient delivery of targeted therapy for CVD
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• In particular, exosomes play an important part in the pathophysiology of
myocardial infarction due to the increased need of orchestrating important
signaling molecules such as chemokines, growth factors and miRNAs
involved with hypoxic stress of cardiomyocytes.
• Secretion of exosomes has been shown to be involved with cardioprotection
and remodeling of the heart after ischemic in the compensatory and repair
process, acting as paracrine signaling mediators.
• They may also play a role in stimulating angiogenesis and promoting
cardiomyocyte survival in stem cell therapy
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Novel drug eluting and dissolvable stent
• Stent implantation has become a standard practice in interventional
cardiology. In the past decades, major efforts have been made to improve
implantation technique and stent design, and significant advances have been
made from traditional balloon angioplasty and bare-metal stents.
• One major revolution includes the development of drug eluting and
dissolvable stents, also called Bio-Resorbable Scaffolds (BRSs). Drug-
eluting stents are a novel approach to allow local drug delivery to prevent in-
stent restenosis.
• Furthermore, dissolvable stents are a novel development, which allow stents
to act as a temporary scaffold, permitting increased natural healing and
decreasing risk of thrombosis
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• Nonetheless, although with its advantages, certain risks still remain.
• Different materials have been used to make BRS such as poly-l-lactic acid
(PLLA) and magnesium being the most common. Each material has different
strengths, resorption time, thrombotic properties and corrosion, and
degradation rate.
• The first BRS to be used was the Igaki-Tamai stent, which is self-expandable
upon heating and continues to expand until equilibrium between dilation and
resistance of vessel wall is reached.
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Immunotherapy
• Chronic inflammation and abnormal immune responses have been shown to
be an integral part in the development of CVD.
• Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus
erythematosus, scleroderma are well-defined chronic inflammatory diseases
that also greatly affected by the cardiovascular system.
• Interestingly, there is growing understanding of the interaction between
metabolism and inflammation through the interaction of lipids and
leukocytes.
• Circulating monocytes, neutrophils, and platelets also have played an
important role in CVD disease initiation and progression
• Understanding the immune origins may delineate novel mechanisms to
identify targeted immunotherapy for prevention and management of heart
disease.
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• For example, RA is an autoimmune disease in which cytokines such as
tumor necrosis factor (TNF) and interferon attack normal, healthy
cardiomyocytes. This results in dysfunction of endothelial lining of coronary
blood vessels, leading to lipid deposition, plaque accumulation,
atherosclerosis and an increased risk of thrombosis.
• RA and CVD have many similar innate and adaptive immune response
mechanisms such as chronic elevation of acute phase reactant proteins,
cytokines, and a common cell-mediated immune response
• Many anti-inflammatory agents have been shown to be promising in the
management of CVD. For example, the use of methotrexate, a disease-
modifying anti-rheumatic drug used to treat many chronic inflammatory
disorders, has been shown to be associated with lower risk for CVD in
autoimmune disease states
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• Anti-TNF-α therapy (infliximab), another staple drug used to treat RA, has
been shown to reduce risk of all cardiovascular events, myocardial
infarction, and cerebrovascular accidents
• Other anti-inflammatory therapeutics such as IL-1, IL-6, and T- and B- cell
inhibitors (Rituximab) are also of interest due to their potential in reducing
inflammation in CVD
• However, anti-inflammatory agents have also been shown to increase other
health risks such as increase total cholesterol and triglycerides as well as
alter hematopoiesis and stem cell proliferation
• Current trials are on-going in order to better understand how anti-
inflammatory drugs and immunotherapy should be used in the prevention
and management of CVD.
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Nanomedicine
• Recently, nanomedicine has been extensively investigated for the diagnosis
and therapy of CVDs
• Its unique design allows for precise structure control and targeted drug
delivery, making it an effective method to treat a range of CVDs
• Several types of drug delivery systems have been utilized depending on the
therapeutic agent of choice and disease state. Therapeutic agents include a
variety of small molecules and more recently DNA, siRNA, peptides and
proteins.
• Drug delivery systems, including nanoparticles and liposomes, are highly
dependent on drug-inherent properties such as solubility, molecular weight
and the therapeutic goal of the drug.
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