ISSN (Print): 1871-529X
ISSN (Online): 2212-4063
Volume 19, 4 Issues, 2019
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ISSN (Print): 1871-529X
ISSN (Online): 2212-4063
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16 Articles Ahead of Print are available electronically
Cardiovascular and hematological disorders are the most common diseases afflicting humans. The aim of this mini thematic
issue entitled “Recent Advancements in Identification of Novel Drug Targets and Drug Delivery for Cardiovascular and
Hematological Disorders” is to summarize the recent advancements regarding the identification of novel drug targets and drug
delivery techniques in cardiovascular and hematological disorders. It presents a compilation of updated articles written by the
researchers with the comprehensive understanding in this field.
Diabetes is treatable, but even when glucose levels are under control it greatly increases the risk of cardiovascular disease
and stroke. This predisposition is because people with diabetes, particularly type 2 diabetes, may have hypertension, obesity or
abnormal cholesterol conditions that contribute to their risk of developing cardiovascular disease. Cardiovascular Disorders
(CVD) are the foremost reasons for morbidity and mortality amongst diabetic populations. Kumar et al.  have discussed the
interplay role of diabetes in cardiovascular disease. They have highlighted the mechanisms of diabetic associated
cardiovascular disease and the role of Adenosine Monophosphate Activated Protein Kinase (AMPK) enzyme as a potential
target in cardiac hypertrophy, atherosclerosis or heart failure with regards to its cardioprotective potential.
Sarkar and Rafiq  have discussed the role of cellular or humoral immune system and its association with CVD. This
article discusses that the immune cell infiltration to adipose tissue contributes to the production and secretion of the proinflammatory
mediators. This infiltration also promotes both the local and systemic pro-inflammatory that triggers various
inflammatory pathways within cardiac tissue and ultimately leads to cardiac dysfunction. They have specifically highlighted the
role of B-cells and its pathogenesis in heart failure. The study stressed upon identifying novel therapeutic targets along with the
development of newer/better therapeutic strategies to combat the complex problem of CVD.
Another challenge in CVD is Infective Endocarditis (IE). The IE emergence of new antimicrobial agents has shifted the
pattern of pathogens that cause IE. Pseudomonas aeruginosa is one of the emerging pathogens that has been associated with IE.
However, the interaction of P. aeruginosa with Human Aortic Endothelial Cells (HAECs) is not known. The binding and
subsequent invasion of HAECs is one of the most crucial hallmarks of IE. In this issue, Mittal et al.  have demonstrated that
P. aeruginosa can invade HAECs in a dose and time-dependent manner using gentamicin protection assay. It was also observed
by the authors that P. aeruginosa induces cytokine production and cell damage as observed in human clinical conditions. This
model can be of immense importance for high throughput screening of drugs that will prevent P. aeruginosa invasion of
HAECs, cytokine production, and cell damage. The availability of these new drugs will provide novel avenues for the treatment
Although CVD is a leading cause of morbidity and mortality worldwide, there are still drug delivery challenges for the
effective treatment of these disorders. Mittal et al.  reviewed the pathogenesis of atherosclerosis, first-line medical treatment
for CVD, and key obstacles inefficient drug delivery. A better understanding of the molecular mechanisms underlying the
pathogenesis of CVDs will help in developing novel efficacious treatment modalities beyond conventional therapies for heart
Despite advances in medical technology, the conventional therapies for CVD still lack efficacy and site specificity. To
address these concerns there has been an increased interest in the cardiovascular community to develop newer techniques such
as nanocarrier systems that possess the potential to revolutionize the treatment of CVDs. Nanocarrier systems modify the
physicochemical properties of the therapeutic drug and are specific to the targeted delivery site. Further, nanocarrier based
delivery systems can overcome the biological challenges of conventional therapies by a combinatory approach such as drug
delivery along with the added advantage of image-guided therapy for targeted/ personalized treatment known as the
nanotheranostics approach. Gupta et al.  have discussed the role of nanotechnology in the development of novel nanocarrierbased
approaches to improve existing research concerning such nanoparticulate drug delivery systems, their reported
effectiveness and the challenges facing their translation into pervasive clinical use.
In summary, we believe that mini thematic issue will provide the latest information to the researchers and clinicians
working in the field of cardiovascular and hematological disorders. The issue is well within the scope of ‘Cardiovascular &
Hematological Disorders-Drug Targets’ and will be appealing to the audience of this journal. Finally, a special word of
appreciation is due to all the contributors that embraced our challenge and made the present issue possible.
Diabetes mellitus is a major public health disorder that
affects more than 400 million subjects, with a prevalence
ranging from 7.2 to 11.4% in the general population,
worldwide [1, 2]. Diabetes is associated with various
metabolic disorders and vascular damage of great extent 
and thus, the management of the diabetic patient should aim
in the attenuation of hyperglycemia and other concomitant
cardiovascular conditions [4-7].
Current antidiabetic treatment options were unable to
offer consistent cardiovascular benefits. Apart from metformin
and glucagon-like peptide 1 analogues, the rest of the available
hypoglycemic agents have not provided consistent benefits
from the cardiovascular standpoint. Furthermore, the impact
of these drugs on other cardiovascular risk factors is either
neutral or beneficial, and in some cases even harmful [8-15].
Sodium-glucose co-transporters (SGLT) 2 inhibitors are
a novel antidiabetic class of drugs that offer a different
approach for the amelioration of hyperglycemia than the
other antidiabetic drug classes. SGLT-2 inhibitors block the
reabsorption of glucose in the renal proximal tubule,
resulting in decreased glucose reabsorption, increased urine
excretion of glucose and attenuation of glycemic parameters
[16, 17]. Through their unique mechanism of action, SGLT-
2 inhibitors seem to offer several beneficial effects on a
cluster of other cardiovascular risk factors. These drugs are
associated with a mild increase in sodium urine excretion; this
combined with the osmotic effect of the excreted glucose,
results in a mild diuretic effect that leads to hemodynamic
improvements. A mild decrease in blood pressure
accompanied with a mild reduction in body weight is noted
with SGLT-2 inhibition. In addition, beneficial effects with
these drugs are observed in serum acid levels, triglycerides
and high-density lipoprotein cholesterol levels. Ameliorating
effects are also noted in other established cardiovascular risk
factors such as diabetic nephropathy, non-alcoholic fatty
liver disease and arterial stiffness [18, 19].
The pleiotropic effect of SGLT-2 inhibitors on the
aforementioned abundance of cardiovascular risk factors has raised several expectations for their cardiovascular profile.
As of this issue, two cardiovascular studies on these novel
drugs exist and have provided encouraging results.
Empagliflozin in the EMPA-REG study and (to a lesser
extent) canaglifllozin in CANVAS study have shown
remarkable benefits in cardiovascular morbidity and
mortality [20, 21]. Furthermore, SGLT-2 inhibitors seem to
attenuate heart failure and renal outcomes [20-23].
In this special issue of Cardiovascular and Hematological
Diseases-Drug Targets, we aim to present current data on the
multidimensional profile of SGLT-2 inhibitors and discuss
the benefits and potential contradictory findings with this
class of drugs. Manolis et al. discuss in detail the mechanism
of action of SGLT-2 inhibitors and comprehensively explain
the SGLT-2 inhibitors-induced increased excretion of
glucose, sodium, water and of other substances that might
result in important outcome benefits. They further describe
the effect of SGLT-2 inhibition on other organs and systems,
as well . The antidiabetic profile of the drugs is
presented by Kihm et al. in the following review. The
authors report the results from studies of several SGLT-2
inhibitors used as monotherapy or as add-on treatment to
preexisting antidiabetic drugs. They noted a significant
reduction in fasting plasma glucose and glycated hemoglobin
of approximately 0.5 to 1% (in absolutes values).
Importantly, it is stated that SGLT-2 inhibitors are not
inferior to other hypoglycemic drugs in terms of glycemic
control, with insignificant differences in glycated
hemoglobin between SGLT-2 inhibitors-treated patients and
other actively treated groups . Subsequently, Tsioufis et
al. in their review present the blood pressure-lowering effect
of SGLT-2 inhibitors (mostly due to increased diuresis) from
studies with office and ambulatory blood pressure
measurements that range from 3 to 5 mmHg in systolic and 1
to 2 mmHg of diastolic blood pressure. Furthermore, it is
stated that with their use, a mild body weight reduction of 2
to 3 kg is achieved, that is sustained with long-term
treatment . The significant cardiovascular and mortality
risk reductions are reported by Lovic et al. who discussed
the data obtained from the two aforementioned cardiovascular
trials and from one large observational study in
detail. Among the favorable data presented, the authors
report the concerning higher amputation risk observed with Doumas et al. and Papademetriou et al. comprehensively
present data and potential underlying mechanisms of the
attenuating impact of SGLT-2 inhibitors on renal and heart
failure outcomes, respectively [28, 29]. In the article by
Doumas et al. it is stated that SGLT-2 inhibitors are
associated with a significant delay in the progression of
diabetic kidney disease, with empagliflozin and canagliflozin
achieving a remarkable deceleration of estimated glomerular
filtration rate decline (0.9 ml/min/year) and amelioration of
albuminuria status, respectively . Papademetriou et al.
present the benefits of SGLT-2 inhibition in heart failure
outcomes and support that these findings could potentially be
attributed to the ameliorating effect of SGLT-2 inhibitors on
blood pressure, visceral obesity, arterial stiffness, diastolic
dysfunction and importantly to the SGLT-2 inhibitorsinduced
increase in ketones bioavailability . Tziomalos
et al. report in detail the impact of these drugs on stroke risk
factors and the contradictory neutral impact of SGLT-2
inhibitors on stroke risk, implying that other factors may be
in play that need to be unveiled . Last, Karagiannis et al.
discuss the concerns of a potential increase in the risk of
euglycemic diabetic ketoacidosis with this novel class of
drugs. The authors present randomized controlled trials,
meta-analyses, case series and case reports and note that
most ketoacidosis cases were observed in patients with type
1 diabetes, due to off-label use of SGLT-2 inhibitors, or in
patients previously misdiagnosed as having type 2 diabetes,
who in fact suffered from late autoimmune diabetes of adults
The recent CANVAS study provided similar results with
the EMPA-REG trial and suggests a class effect of SGLT-2
inhibitors on morbidity and mortality outcomes. These
remarkable findings could establish this class of drugs as an
optimal second-line treatment option after metformin
monotherapy. The concerning findings in terms of stroke and
amputations risk will place at the epicenter of the scientific
interest, the identification of patients’ groups that might be
more prone to these events, such as patients with increased
hematocrit levels or severe peripheral artery disease. Ongoing
cardiovascular and renal trials will potentially provide
further credence for this novel and very promising class of
The prevalence of cardiovascular and metabolic disease in China has been rapidly increased during last 20 years in parallel
with the rapid industrialization of the country [1, 2]. Hypertension, obesity, unhealthy diet and inactivity lifestyle appear to play
important roles in the boost of heart disease, stroke and diabetes in China [3, 4]. Heart disease is the number 2 cause of death in
Canada . One out 3 of Canadians is diagnosed as diabetes or pre-diabetes . Since 2011, Chinese Atherosclerosis Society
(CAS) and Canadian Society of Atherosclerosis , Thrombosis and Vascular Biology (CSATVB) have organized 5 joint
symposiums which were held in Beijing (2011), Vancouver (2013), Nanjing (2014), Calgary (2016) and Hengyang (2017).
More than 1,000 of researchers, clinicians and trainees from China and Canada presented their research results. The CASCSATVB
joint symposiums become an important platform to develop scientific collaborations between institutes and
researchers in the two countries. The Cardiovascular and Hematologic Disorders-Drug Target journal published two hot topic
issues as the proceeding of those joint symposiums [7, 8]. This special issue selected 4 mini-reviews presented by Canadian or
Chinese researchers and their colleagues on recent joint symposiums.
Dr. Michael Walsh in University of Calgary reported in his plenary lecture on the regulation of smooth muscle myosin light
chain phosphatase by multi-site phosphorylation of the myosin targeting subunit, Myosin phosphatase targeting subunit 1
(MYPT1). Their findings provided deep insight for the phoshphorylation of MYPT1, which may be important therapeutic target
for a number of cardiovascular disorders including chronic heart failure, intestinal inflammation, pulmonary hypertension,
asthma or diabetic vasculopathy .
Dr. Lemin Zheng and his colleagues in Beijing University School of Medicine reported their findings of the involvement of
Connexin 43 and myocardial ischemia-reperfusion injury . Connexin 43 is the major component of cardiomyocyte Gap
Junctions and plays an important role in cardioprotection. Myocardial connexin 43 is upregulated in acute myocardial ischemic
injury and it becomes an emerging therapeutic target for ischemic/perfusion injury of heart.
Dr. Paolo Raggi and his colleague in University of Alberta reported the findings of his group on role of epicardial adipose
tissue in atherosclerosis. Their studies suggest that adipose tissue is an important source for inflammatory mediators, which
play critical roles in the initiation of inflammation on endothelial surface and atherogenesis .
Dr. Huiyong Yin and his colleagues in Shanghai Institute of Life Sciences demonstrated their research progress in the field
of Cholesterol Homeostasis and Liver X Receptor (LXR) in Atherosclerosis. The activation of LXR in liver inhibits cholesterol
uptake and enhances cholesterol efflux. LXR has become a therapeutic target for the treatment of atherosclerosis. Natural LXR
agonists are mostly oxysterol or cytochrome P450. Synthesized LXR agonists have been developed (T0901317 and GW3965).
In contrast, polyunsaturated fatty acids and geranylgeranylpyrophosphate inhibited LXR activity .
Since the reviews have been written between 2016 and 2017, many related studies have been done by now. The studies
described in the thematic issue reflect the rapid progresses in atherosclerosis researches among researchers in Canada and
China. Multiple researchers reported the findings generated from the collaborative studies between the two countries resulted
from previous joint symposiums of CSATVB and CAS. We are looking forward to see more of collaborative researches to be
developed between the researchers and trainees between the two countries and societies.