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Volume 19, 6 Issues, 2021
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Special Issue Submission
DIABETES AND OBESITY IN PREGNANCY: from patients to molecular mechanisms
Guest Editor(s): Luis Sobrevia
Submit Abstract via Email
Novel therapeutic approaches towards the treatment of Vascular diseases
Guest Editor(s): Shams Tabrez
I do want to compliment Bentham on the excellent processing of my manuscripts—the editorial and production works have been outstanding.
In this Special Issue of Current Vascular Pharmacology, emerging risk factors for cardiovascular (CV) disease are reviewed.
CV disease remains the major cause of death worldwide . Therefore, it is important to prevent, diagnose early and
adequately treat CV disease. The use of biomarkers and non-invasive tests to assess inflammation, endothelial dysfunction and
atherosclerosis may help achieve this goal . Furthermore, CV risk stratification may benefit from markers such as the coronary
artery calcium (CAC) . Also, different methods of blood pressure (BP) measurement may predict CV morbidity and
Obesity in childbearing age girls increased worldwide. Obesity and type 2 diabetes mellitus (T2DM) are metabolic disturbances
whose prevalence shake-hands. Pre-gestational maternal obesity is a condition that associates with foe to placental vascular
dysfunction compromising the supply of nutrients to the developing fetus. Similar alterations are seen in this vascular bed
in pregnant women that develop gestational diabetes mellitus. Along with the multiple factors increasing the risk of GDM are
pre-gestational maternal obesity, maternal supra physiological gestational weight gain, being obese and having developed GDM
in a previous pregnancy. The mechanisms behind these alterations include insulin resistance, dysregulation of metabolic pathways
such as L-arginine/nitric oxide signaling, adenosine/L-arginine/nitric oxide (ALANO) signaling, arginases/urea, inflammation,
or endoplasmic reticulum stress. Worryingly, obesity and diabetes in pregnancy results in newborns that were in utero
programmed for the development of child/juvenile or adult diseases showing higher risk of cardiovascular disease, obesity,
overweight, and T2DM. Whether these alterations may be prevented by treating the women before they get pregnant or treating
pregnant women in a more efficient manner is not fully unveiled. The articles in this thematic will board the consequences at a
cellular and molecular aspects of maternal obesity (before and during pregnancy), diabetes mellitus (pregestational and gestational),
gestational diabesity (i.e. obese women that present with gestational diabetes mellitus). Clinical aspects of the mothers
and children and protocols for the treatment of these diseases in pregnancy are also discussed. Since the clinical information of
the patients correlate with metabolic parameters at a cellular and systemic level, several pieces of evidence addressing the
pathophysiology of the obesity and diabetes in pregnancy will be opened for discussion.
The risk of cardiovascular (CV) morbidity and mortality goes hand in hand with the decline in estimated-glomerularfiltration-
rate (eGFR) and the severity of albuminuria [1, 2]. In fact, the incidence of myocardial infarction and probability of
CV death among patients with chronic kidney disease (CKD) is comparable with that of patients with established coronary artery
disease and even higher than that of patients with diabetes mellitus [3, 4]. Accordingly, CKD should be considered as a
coronary artery disease equivalent.
The burden of CV disease is multiple-fold higher among patients with end-stage renal disease (ESRD) receiving maintenance
dialysis . The 5-year survival rate of ESRD patients ranges from 40 - 50%, with more than half of the deaths being
directly attributable to CV causes . Despite the fact that the overall mortality rates for ESRD patients have declined over the
past 2 decades, this improvement in age-specific survival was not consistent with the much greater increment in age-specific
life expectancy observed in the general population [7,8]. This thematic issue of Current Vascular Pharmacology is devoted to
exploring the contribution of traditional and non-traditional risk factors to the pathogenesis of CV disease in patients with
Hypervolemia is traditionally an established risk factor for CV complications and all-cause mortality in dialysis patients.
The exposure of these patients to the risks arising from chronic volume overload is common, most likely because the assessment
and management of dry-weight in daily clinical practice continues to be guided by subjective clinical judgment . Covic
and Siriopol , explore the potential role of more objective methods/tools (such as inferior-vena-cava diameter, bioimpedance
spectroscopy, relative blood volume monitoring, lung ultrasound B-line score, etc.) in the detection of subclinical volume
expansion. This article considers the advantages and disadvantages of these techniques over usual care in the management of
Uncontrolled hypertension, confirmed by home or ambulatory blood pressure (BP) monitoring, is a common manifestation
of volume overload in patients on dialysis. When initial management of hypertension based on sodium restriction and dryweight
reduction is ineffective, the administration of antihypertensive drugs is the second-line therapeutic approach to achieve
BP control. Georgianos and Agarwal , provide an overview of randomized controlled trials testing the safety and efficacy
of different antihypertensive drugs in the dialysis population. In sharp contrast with the general hypertensive population, emerging
evidence suggests that among those on dialysis, β-blockade — particularly atenolol administered on a thrice-weekly regimen
immediately post-dialysis — is more effective than an angiotensin-converting-enzyme-inhibitor based regimen in controlling
interdialytic hypertension and in preventing the occurrence of adverse CV events .
Observational studies have shown that among patients receiving conventional thrice-weekly haemodialysis, hyperkalaemic
episodes, hospitalizations due to heart failure/cardiac arrhythmias or even fatal events occur more commonly on the day after
the long (3-day) interdialytic interval than on any other day . The mechanistic background of this “day-of-the-week” effect
on CV morbidity and mortality remains unclear, but cyclic shifts in volume status and metabolic parameters arising from the
intermittent nature of renal replacement therapy may be important mediators . Roumeliotis et al. , explore the potential
CV benefits of extended-time, nocturnal haemodialysis, which is an intensified dialysis regimen that may mitigate the adverse
effects related to the long interdialytic period of conventional haemodialysis. Conversion from conventional to extended-time
nocturnal haemodialysis has been associated with improvements in several surrogate CV risk factors . Randomized trials
are warranted to prove the superiority of nocturnal over conventional hemodialysis on “hard” clinical outcomes.
With respect to the pathogenesis of CV disease, vascular remodeling in ESRD is characterized by long-term structural alterations
mediated through the atherosclerotic and arteriosclerotic process . Formation of atheromatous plaques with restriction
of blood flow and downstream ischaemia of tissues and organs impairs conduit arterial function, thereby causing ischaemic
CV events. Structural alterations in visco-elastic properties of the biomaterial constituting the media of the arterial wall impair the cushioning or dampening of arterial function . Arteriosclerosis is considered as the main underlying mechanism of
isolated systolic hypertension, left ventricular hypertrophy, congestive heart failure and sudden death . Acceleration of
these structural arterial alterations can only partially be explained by the accumulation of traditional CV risk factors in patients
with ESRD .
Oxidative stress occurs from the early stages of CKD and is progressively augmented in parallel with the decline in eGFR.
Among patients with ESRD, the dialysis procedure per se further aggravates the oxidant-antioxidant imbalance. Roumeliotis
et al.  investigated the role of oxidative stress in the pathogenesis of atherosclerosis and summarized evidence from studies
testing whether exogenous antioxidant supplementation (i.e. vitamin E and C, statins, omega-3 fatty acids and Nacetylcysteine)
is effective in retarding the progression of CV disease in ESRD. The deleterious effects of oxidative stress go
hand-in-hand with sub-clinical vascular inflammation, a process mediated through the increased expression and up-regulated
activity of specific cell subsets of the innate immune system. Dounousi et al.  point out that advanced CKD represents a
typical clinical state characterized by persistent systemic inflammation. Their review explores the complex interplay of natural
killer cells and natural killer T cells with atheromatosis in ESRD .
Disturbances in mineral metabolism within the frame of secondary hyperparathyroidism represent another mediator of
adverse vascular remodelling in ESRD. Memmos and Papagianni , provide evidence from experimental studies showing
that fibroblast growth factor-23 and soluble Klotho are implicated in phenotypic transformation of vascular smooth muscle cells
into osteoblastic-like cells, thus acting as promoters of the vascular calcification process. This process is down-regulated by the
action of endogenous inhibitors of vascular calcification. Roumeliotis et al. , describe the biological actions of Matrix Gla
Protein, a small vitamin K-dependent molecule that maintains minerals in a soluble form and inhibits their deposition in the
media of the arterial wall. Since the activation of Matrix Gla Protein is determined by the vitamin K status, it is not surprising
that observational studies have associated vitamin K deficiency with progression of the vascular calcification process and with
higher risk for CV morbidity and mortality in several patient populations, including those with ESRD .
From a clinical standpoint, non-invasive assessment of the aortic pulse wave velocity (PWV) represents the “gold-standard”
measure of the severity of arteriosclerotic damage . Georgianos et al.  provide an overview of prospective observational
studies that explored the prognostic significance of arterial stiffness in patients with ESRD. Although “historical” cohort studies
associated aortic PWV with higher risk of all-cause and CV mortality, more recent studies incorporating state-of-the-art statistical
methodology showed that the addition of aortic PWV to standard risk factor scores could not improve CV risk stratification
and reclassification . Therefore, more conclusive evidence regarding the role of aortic PWV as a tool to guide CV risk factor
management in patients with ESRD is warranted.
In conclusion, this thematic issue provides an overview of the complex pathophysiology of CV disease in ESRD, offering
insights and generating hypotheses for future research.
In Part 1 of this Thematic Issue entitled “Systemic Autoimmune Rheumatic Diseases and Cardiology”, a
panel of specialists and experts in cardiology, rheumatology, immunology and related fields discussed the cardiovascular
complications of spondyloarthritides, rheumatoid arthritis, Sjogren’s syndrome and vasculitides, as well as relevant cardiovascular
issues related to non-biologic and biologic disease-modifying anti-rheumatic drugs (DMARDs), and provided
their recommendations for prevention and management of these complications. In part 2 of this Thematic Issue, experts
discuss the enhanced cardiovascular risk conferred by additional autoimmune rheumatic diseases (ARDs), including systemic
lupus erythematosus, the antiphospholipid syndrome, psoriasis and psoriatic arthritis and juvenile idiopathic arthritis.
These, and the previous articles, place inflammation as the key common link to explain the enhanced risk of cardiovascular
complications in patients with ARDs. It follows that treatment should probably target inflammation. From all
these contemporary reviews, the conclusion that is derived further supports the notion of the emerging field of Cardio-
Rheumatology where physicians and experts from these two disciplines collaborate in risk stratification and optimization
of preventive strategies and drug therapies in patients with ARDs.
Systemic Autoimmune Rheumatic Diseases and Cardiology - Part 1
Aging is a universal biological process that leads to progressive and deleterious changes in organisms. Slowing aging is
always a popular research area. Nowadays, the meaning of slowing aging has changed from simply prolonging lifespan to an
emphasis on quality of life. The concept of healthy aging and prevention of pathological aging, which is associated with diseases,
including cardiovascular diseases (CVDs), is responsible for a large number of deaths worldwide. CVDs can be associated
with a number of aging-associated conditions, which contribute to increased cardiovascular risk, such as hypertension,
dyslipidaemia, obesity and type 2 diabetes, insomnia or cognitive disorder in aging populations [1, 2].
Herbal medicine (HM) has a long history in Asian countries. It is believed that many HMs, such as ginseng, radix astragali,
ganoderma or gingko and herbal medicinal compounds have anti-aging properties. Recent studies have shown that some medicinal
herbs are effective in intervention or prevention of aging-associated cardiovascular risk or cognitive disorder, but the
mechanisms and safety remain unclear [3, 4]. This special issue entitled “Herbal Medicine for Slowing Aging and Cardiovascular
Risk: Mechanisms and Safety”, consists of 7 articles describing the use of HM and the mechanisms or safety involved for
aging-associated cardiovascular risk or cognitive disorder.
Cheng et al.  reports the potential role of HM and non-pharmacological therapies in the treatment of insomnia and summarizes
the scientific evidence reported from 2008 to 2018. Based on this evidence, HM may be applicable in clinical settings.
The combination of acupuncture and herbs should also be emphasized in clinical practice, in order to prevent adverse reactions
and drug-dependence as observed with some Western medications in the treatment of insomnia.
Kim and Kang  summarize the clinical evidence on the benefits of herbal drugs and proposes an evidence map outlining
their effects on vascular dementia (VaD) based on systematic reviews. HMs used individually or in combination with Western
medicine might lead to benefits for VaD patients. However, there is still room for further evaluation of the evidence and the
mechanisms of the action involved.
Zhang et al.  systemically summarizes the effects and potential mechanism of Chinese Medicines on inhibiting advanced
glycation end products (AGEs)-related aging diseases. Five classes of components from Chinese Medicines have been found to
be effective in reducing AGEs-mediated damage (e.g. flavonoids, saponins, polysaccharides, alkaloids and polyphenols). Anti-
AGEs action might be one reason why Chinese Medicine may have anti-aging diseases effects.
Li et al.  discuss the pathophysiological alterations in aged vasculature and the underlying mechanisms of Ginkgo biloba
extract (GBE) in vascular aging inhibition. The main effects of GBE in aged vasculature might be associated with longevity
signaling pathways. GBE also attenuates the progression of vascular aging in diabetes mellitus via regulation of glucose and
Yang et al.  systematically summarize the pharmacological activities of U. rhynchophylla (UR, a common Chinese HM
known as Gou-teng in Chinese) and its major components on central nervous system (CNS). UR and its major components,
such as alkaloids, flavonoids and terpenoids, have beneficial effects on CNS diseases via acting on various risk factors and biochemical
pathways involved in CNS disease pathogenesis.
Wang et al.  reviewed the mechanisms of the active ingredients of Rhizoma coptidis and Rhizoma coptidis-containing
Chinese herbal compounds in the treatment of Alzheimer’s disease (AD) and VaD. The “One-Molecule, One-Target” paradigm
has suffered heavy setbacks, but a “multitarget-directed ligands” strategy may be viable. Rhizoma coptidis active ingredients
and Rhizoma Coptidis-containing Chinese herbal compounds have potential multi-aspect therapeutic effects for AD and VaD.
Phu et al.  focused on the efficacy, mechanisms, and safety of some of the most recognized HMs (e.g. Ginseng, Radix
astragali, Ganoderma lucidum, Ginkgo biloba and Gynostemma pentaphyllum), describing and critically analysing their effect
in slowing aging and aging-associated diseases such as cognitive impairment and cardiovascular risk.
These 7 articles highlight the latest evidence regarding the use of HM and the mechanisms or safety involved for agingassociated
cardiovascular risk or cognitive disorder.
Lower extremity artery disease (LEAD) is a leading cause of atherosclerotic vascular morbidity in Europe, being even more
prevalent that coronary artery disease (CAD) . Importantly, LEAD is an established independent risk factor for cardiovascular
(CV) mortality and morbidity [2-4], particularly in its advanced stages, i.e. in patients requiring lower limb revascularisation
[5, 6], and in patients suffering from chronic limb-threatening ischaemia (CLTI) . The strong association between LEAD and
CAD, with at least one-third of LEAD patients having history and/or electrocardiographic signs of associated CAD, and with
up to 70% showing significant disease at coronary angiography [8, 9], has led to the identification of LEAD as a high-risk subgroup
in all randomised trials focussed on CAD [4, 10-14]. Given the great advances in the treatment of CAD over the last decades,
clinical research in this field is currently focussed on addressing “residual risk” in patients suffering from CAD. Therefore,
being a marker of worse prognosis in CAD patients, LEAD has attained a growing interest from the community of Cardiologists,
leading to the issue of guidelines on the management of peripheral arterial diseases from the European Society of Cardiology
(ESC), firstly in 2011  and again in 2017 .
Most recently, LEAD attained the same “dignity” as CAD in the large randomised COMPASS (Cardiovascular Outcomes
for People Using Anti-coagulation Strategies) trial, where patients suffering from LEAD (or from carotid artery disease) were
enrolled independent of the presence of coexisting CAD, i.e. LEAD was not a subgroup of CAD but a distinct disease category
. In COMPASS, rivaroxaban 2.5 mg twice daily on top of aspirin was more effective in reducing the risk of major CV
events in the peripheral artery disease population compared with the CAD population, and was also associated with an impressive
46% reduction in major adverse limb events (acute and chronic limb ischaemia including major amputation) . On the
other hand, the risk of major bleeding was also increased with the dual antithrombotic regimen, highlighting the need for a careful
estimation of the bleeding risk of individual patients before embarking in more potent antithrombotic treatments. Based on
COMPASS results, low-dose rivaroxaban may soon be proposed as standard of care in patients with stable LEAD who are not
at high risk for bleeding. This may have a potentially huge impact on public healthcare costs, considering the current pricing of
the drug and the prevalence of LEAD in an ageing population. In this setting, cost-effectiveness analysis should be regarded as
a powerful tool in the hands of the clinicians when dealing with public health stakeholders and decisions bodies, because it enables
us to assess whether a new treatment is cost-effective - and thus affordable - for the community, on top of being clinically
effective . As a matter of fact, two recent cost-effectiveness analyses of the COMPASS trial performed from an Australian
perspective showed that low-dose rivaroxaban is cost-effective in the vast majority of the scenarios explored, and even more so
in patients with LEAD  compared with patients with CAD .
A further source of interest for LEAD in recent years was represented by the rapid development of endovascular revascularisation
techniques, leading to an exponential increase in the number of patients undergoing lower limb revascularisation (currently
80% of cases undergo endovascular procedures) . Such growth in the interventional treatment of LEAD was accompanied
by a large number of clinical studies, including randomised trials, enrolling patients with LEAD; however, the vast majority
of these trials are focussed on the evaluation of short-term outcomes of endovascular devices and techniques, leaving
wide gaps in evidence to be filled by future studies. In particular, very little evidence is available on the best antithrombotic
treatment following lower extremity revascularization.
In this context, it is my belief that it is now prime time for LEAD on the stages of both clinical research and clinical practice
in the field of atherothrombotic vascular diseases. A sign of these times is the quick growth of the Working Group on Aorta and
Peripheral Vascular Diseases of the ESC, which I had the honour to chair . It was within this scientific community that the
idea of the present special issue of Current Vascular Pharmacology was conceived. This issue, dedicated to antithrombotic
therapy in patients with LEAD, represents a vehicle for the dissemination of knowledge in the field of LEAD, hopefully contributing
to a better understanding and management of LEAD patients in clinical practice. To increase the awareness and
knowledge of LEAD is actually the mission of the Working Group on Aorta and Peripheral Vascular Diseases of the ESC. The
need for an awareness campaign on LEAD is proven by recent epidemiologic studies, showing that a large proportion of patients
with LEAD does not yet receive guideline-recommended secondary prevention therapy, with antiplatelets and angiotensin-
converting enzyme inhibitors or angiotensin-receptor blockers being prescribed to <50% of the patients and statins to
only two thirds .
The mainstays of guideline-recommended pharmacological treatment of LEAD include antiplatelets (with clopidogrel as
first choice), statins, and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers . Antithrombotic therapy
was chosen as the topic of this special issue because of its prominent role in the prevention of CV events and of limb events
in patients suffering from LEAD, which is not associated with exhaustive evidence regarding the choice of drug(s) and treatment
duration in the numerous clinical settings that make up the wide spectrum of LEAD. In this issue of Current Vascular
Pharmacology we will cover all aspects of antithrombotic therapy in patients with LEAD, from the pathophysiology of thrombosis
to the assessment of the bleeding risk.
Habib, et al., provide a comprehensive description of the pathophysiology of vascular athero-thrombosis in LEAD, including
an in-depth analysis of the interplay between pro- and anti-thrombotic vascular receptors, and of the contribution of platelets and
circulating coagulation factors in triggering the pro-thrombotic response . In particular, the role of nitric oxide, prostanoids and
endogenous purines is described with a translational approach, along with the consequences of the disruption of the protective
pathways and with the mechanisms of action of the numerous pharmacological agents that are active along these pathways.
Vrsalovic and Aboyans review the available clinical evidence on antithrombotic therapy in patients with LEAD . This
review covers the full spectrum of clinical scenarios of LEAD, from asymptomatic to chronic limb-threatening ischaemia. In
particular, the role of single and dual antiplatelet treatment is discussed, as well as the role of oral anticoagulants, with a specific
focus on the results of the COMPASS trial with low-dose rivaroxaban. The authors also address the clinically relevant
issue of LEAD patients requiring antithrombotic regimens for concomitant CV diseases, such as atrial fibrillation and CAD,
offering a balanced point of view on the management of these patients.
The third paper, which I authored together with Angelillis and Liga, offers an updated overview of antithrombotic therapy
in patients undergoing peripheral revascularisation, both endovascular and surgical. We start with a description of the indications
and techniques of lower extremity revascularisation, and proceed with in-depth analysis of the available evidence regarding
type and duration of antiplatelet and anticoagulant treatment following endovascular and surgical revascularisation . A
specific focus is dedicated to endovascular revascularisation, whose growth in numbers has not been accompanied by a parallel
growth in high-quality scientific evidence, particularly regarding antithrombotic therapy, which is substantially extrapolated
from the coronary field. Given the lack of randomised trials comparing different antithrombotic regimens and durations across
the wide range of indication, location and modality of peripheral revascularisation, we pragmatically analyse and compare the
antithrombotic strategies chosen by the experts leading the randomised trials dedicated to endovascular devices and techniques.
Lastly, Alatri and Mazzolai provide an in-depth review of how to assess the bleeding risk of our patients, in the era of precision
medicine . In fact, while we strive to reduce local and systemic thrombotic events in patients with LEAD by using new antithrombotic
regimens, we should avoid exposing them to an excess in bleeding risk, tailoring antithrombotic regimen on the individual
patient’s clinical setting. It is therefore of the utmost importance to understand the numerous scores for the prediction of inhospital
and long-term bleeding events that have been developed in various clinical settings. In particular, the authors describe the
bleeding risk scores for patients receiving oral anticoagulants, single antiplatelet therapy and dual antiplatelet therapy.
In summary, I believe that the present special issue of Current Vascular Pharmacology may be useful as an ensemble, providing
a comprehensive outlook on all the aspects of antithrombotic therapy in patients with LEAD. On the other hand, each
review may be also regarded as a stand-alone expert advice on the specific topic covered, providing insights and guidance for
both researchers and clinicians.
Diabetes mellitus (DM) is a very prevalent disease worldwide [1-3]. It holds an outstanding position among non commutable
diseases with an increasing prevalence trend and mortality [1-3]. In particular:
• 1 in 11 adults has diabetes (425 million).
• 1 in 2 adults with diabetes is undiagnosed (212 million).
• 1 in 6 births is affected by hyperglycaemia in pregnancy.
• Over 1 million children and adolescents have type 1 diabetes.
• Two-thirds of people with diabetes live in urban areas (279 million).
• Two-thirds of people with diabetes are of working age (327 million).
• In 2012 alone diabetes caused 1.5 million deaths.
• 3/4 of people with diabetes live in low and middle income countries.
• 12% of global health expenditure is spent on diabetes ($727 billion) [1-3].
Diabetes is associated with micro- and macrovascular complication. Microvascular complications include diabetic nephropathy,
neuropathy, and retinopathy . Macrovascular complications of DM include peripheral vascular disease, myocardial
infarction, stroke, and congestive heart failure [5, 6]. The epidemic of DM, its complications, and their impact on morbidity and
mortality have become a massive global problem and need effective control [4-7].
There is a significant deficit in understanding the risk of DM‐related complications, both by a lot of patients and by some
physicians . Patients with DM, mainly those from ethnic minorities, were often unaware of the risks of complications, especially
for macrovascular events . In a large study, nearly 70% of people with T2DM did not know that they were at increased
risk for developing CVD more than the general population .
The aim of this special issue of Current Vascular Pharmacology is to provide an up-to-date overview about the risks of DM
complications and the effect of newer antidiabetic dugs, the new kids on the block, to avoid them, improving the quality of life
at the same time. These drugs range from selective PPAR modulators [SPPARMs] and dual PPAR agonists to the available
glucagon like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose co-transporter-2 inhibitors (SGLT2i).
Thiazolidinediones (TZDs) are useful, especially the novel selective PPAR-γ modulators, which increase adiponectin without
significant weight gain . SPPARMs and dual PPAR agonists may play an important role in the treatment of CVD disorders
due to lipid-modifying, anti-inflammatory and insulin-sensitizing effects . INT131, a SPPARM-γ with predominantly
insulin-sensitizing actions, may also have favourable lipid-modifying effects . INT131 achieved a high level of antidiabetic
action by an increase in insulin sensitivity that led to reduction in substantial glucose and insulin levels, without noteworthy
adverse effects . Besides SPPARMs, there are dual PPAR agonists too. Elafibranor is a PPAR-α/δ agonist, which was investigated
in a phase 2 trial in 274 (107 with T2DM) patients with biopsy-proven non-alcoholic steatohepatitis (NASH) .
Elafibranor and lobeglitazone , resolved NASH in a significant percentage of patients without fibrosis and improved the
hepatic and metabolic profile, glucose and lipids levels .
Microvascular complications are common and are mainly related to glycemic control . The new antidiabetic drugs contribute
to glycemic control and have their share in preventing or treating microvascular complications .
In regard to macrovascular complications the new antidiabetics GLP-1 RA, commercially available, include liraglutide, exenatide,
lixisenatide, and dulaglutide, which are used for the treatment of T2DM . In the Liraglutide Effect and Action in
Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial, liraglutide reduced the composite endpoint of all
CVD events (mainly myocardial infarction and stroke) and CVD death as well as all-cause mortality in comparison with placebo
. Patients with a GFR < 60 ml/min/1.73 m2 benefited the most. Since NAFLD was not evaluated in this study, a posthoc
analysis would be important . In animal models, administration of the GLP-1 Exendin-4 reduced systemic hypertension
and albuminuria as well as ameliorated biopsy-proven renal damage .
In the EMPA REG study, the primary composite endpoint (death from CVD causes, myocardial infarction, or stroke) was
reduced by 15% with empagliflozin, p=0.04 for superiority . The hospitalization for heart failure had a 35% and death from
all causes a 32% risk reduction . In the EMPA-REG Renal study, renal function (diabetic nephropathy, a microvascular
complication of DM) was substantially improved (less nephropathy worsening, less doubling of the serum creatinine level and
less renal kidney replacement therapy) .
The above suggest that there are indeed new kids on the block that might substantially control glycemic control, micro-, and
macrovascular complications, leading to a considerable reduction in morbidity and (for the first time) mortality. These drugs
are commercially available to be used and all we need is a better education of patients and physicians.
Towards this direction, this issue of Current Vascular Pharmacology covers several topics in the fields of prevalence, identification,
scouting, and mainly treatment of diabetes mellitus complications.
Lovic et al.  describe the growing epidemic of diabetes mellitus according to its types, discuss the contributors for the
continuous increase in its prevalence, and critically evaluate existing epidemiological data. Viigimaa and colleagues  report
the macrovascular complications of type 2 diabetes mellitus (T2DM), including the heart and brain consequences of long-term
hyperglycemia. Faselis et al. reviewed the microvascular complications of T2DM , including the traditional ones (diabetic
nephropathy, neuropathy, and retinopathy) and critically discussing sexual dysfunction as an emerging multifactorial microvascular
complication of diabetes mellitus. Patoulias and colleagues  report the current status and the future perspectives on the
treatment of pharmacological management of cardiac disease in diabetic patients. They provide a really fresh look of this topic,
since they initially discuss the effects of intensive versus standard therapy of its cardiovascular risk factor, and then they critically
evaluate the cardiac effects of each class of therapeutic agents. Papademetriou and colleagues  report recent data on
pharmacological management of diabetic nephropathy, the most prominent microvascular complication of diabetes mellitus,
critically evaluating all available evidence in this field and providing their own expert opinion on the advantages and disadvantages
of relevant trials. Didangellos, Kantartzis  review whether insulin for the treatment of diabetes in patients with heart
failure is an enemy or a friend? They provide available experimental and clinical evidence on the effects of hyperglycemia and
hyperinsulinemia on heart failure, and they conclude that hyperglycemia seems to be the main contributor for heart failure,
while insulin does not seem to be the main contributor. Didangelos, Veves  report the recent data on the treatment of diabetic
neuropathy, and they provide their expert opinion on available and future therapeutic options for this devastating microvascular
complication of diabetes mellitus. Alvaro-Afonso and colleagues  report the existing data on the advances in
dermoepidermal skin substitutes for diabetic foot ulcers. They systematically reviewed 28 randomized controlled trials comparing
the effects of dermal substitutes (either cellular or acellular) on the course of diabetic foot ulcers. Athyros and colleagues
 analyzed the recent developments on pharmacological management of non-alcoholic fatty liver disease in T2DM, a frequently
overlooked comorbidity in patients with type 2 diabetes mellitus. They discuss the effects of traditional and new antidiabetic
drugs on steatohepatitis, and they critically evaluate available evidence on emerging drugs such as SPPARMs.
We hope that this special issue if CVP will contribute to the improvement of physicians approach for the management of
diabetes to offer a proper and evidence-based treatment that will ameliorate the CV profile of the diabetic patient.
This issue aims to provide a comprehensive overview and current knowledge regarding the
association between menopause and cardiovascular risk, with special report on menopausal hormone therapy
(MHT, risks and benefits). This issue also covers special topics, such as premature ovarian insufficiency,
peri-menopause, calcium and vitamin D supplementation, non-MHT refimen and non-alcoholic fatty liver
Insulin is a key hormone involved in the modulation of vascular tone. Several diseases with
altered response to this hormone show with dysregulation of vascular tone, hypertension, and abnormal regulation
of substrates transport and membrane receptors signaling. Insulin therapy, insulin resistance and vascular
dysfunction in pregnancy diseases and other disorders such as hyperglycaemia, obesity, metabolic syndrome,
kidney diseases, lipid disorders, cancer, angiogenesis, lipid metabolism, oxidative stress, has not been well
summarized in the literature. This special issue covers the cellular alterations and metabolism of vascular cells in a
context of insulin resistance.
Cardiovascular diseases are the primary cause of early death and disability in Western countries. The control of
blood cholesterol levels (total and low-density lipoprotein cholesterol) within the limits recommended by the current
guidelines, is one of the cornerstones of the ischemic heart disease therapy. Statins are among the most widely
used drugs in the fight against cardiovascular diseases, as they can reduce blood cholesterol levels. Furthermore,
the ancillary effects of statins, the so-called pleiotropic effects, extend the range of therapeutic indications to other
conditions different from the ischemic heart disease.
There are several statins available to the physician. Although they share the same principle of action, differences in
the chemical composition and in pharmacokinetics (absorption, distribution, excretion and drug-drug interaction)
influence therapeutic and adverse effects. Moreover, cost/benefit analysis limits the use of some molecules only to
certain categories of patients.
The aim of this mini-thematic issue is to give a full overview of statins available on the market, analyzing their main
features, with strengths and weaknesses, in order to provide the clinician with a useful tool in daily practice.
Aims & Scope:
Cardiovascular (CV) disease is a leading cause of morbidity and mortality in both the developing and
developed world. Beside traditional risk factors, several genetic and epigenetic factors are also involved in
the development of atherosclerosis.
Dyslipidaemias are the most studied risk factor for CV diseases. Beside familial hypercholesterolaemia, one of
the most prevalent forms of inherited disorders of lipid metabolism, rare variants of dyslipidaemias have also
an important impact on the prevalence of CV diseases. Additionally, genetic variants have also impact on the
action of the drugs (pharmacogenetics).
Management of atherosclerosis should be focused directly on the arterial wall. Additionally, novel
anticoagulants are expected to have an important role in the treatment of atherosclerosis. A personalized
approach using different “omic” technologies may optimize the efficacy of drug treatment, and
pharmacogenetics are expected to play an important role in this regard.
Keywords: atherosclerosis; diabetes mellitus; genetics; genetic variability; screening; rare genetic
variants; direct anticoagulants; P2Y12 receptor blockers; drugs, Caveolin-1; personalized medicine
Strong inhibition of platelets and thrombin generation at the time of Percutaneous Coronary Intervention (PCI) is essential
to reducing the risk of acute stent thrombosis and may also reduce the risk of restenosis. In this thematic issue, reviews take us
from the pre-PCI scenario, through the peri-operative PCI setting, to short- and long-term out-patient antithrombotic pharmacotherapeutic
options. Arguably the most challenging and high-risk patients presenting to the cath lab are those with severe
aortic stenosis or cardiogenic shock and enhanced bleeding and thrombotic risk requiring individual antithrombotic regimens.
This thematic issue also addresses the challenges faced in the management of these high-risk patients and discusses available
There is no situation where this is more important than in the setting of primary PCI (PPCI) for ST-elevation myocardial
infarction. Yet it would appear that administration of opiate-analgesia for pain relief in patients with STEMI delays gastric
emptying and may impair absorption of orally administered P2Y12 receptor antagonists. A thorough review of the literature in
this issue reveals pharmacokinetic data showing both reduced platelet inhibition and delayed effect of P2Y12 receptor antagonists
with co-administration of morphine. Although randomised controlled trials are lacking, small nonrandomised studies suggest
this combination therapy results in larger infarct size. This concern raises the need for additional anti-platelet pharmacotherapy,
over and above oral P2Y12 receptor antagonists in patients presenting with STEMI who require opiate analgesia.
Whilst awaiting the results of definitive trials, the use of intravenous platelet inhibitors, in high risk patients such as those undergoing
PPCI, should be considered early.
In this regard, cangrelor, a relatively novel intravenous P2Y12-receptor inhibitor with immediate on-and offset of platelet
inhibition appears very attractive. The cost of cangrelor is prohibitive of routine peri-PCI use, and in a detailed review of the
potential pharmacokinetic effect and the clinical trials using cangrelor, it would appear to have a clear role in urgent revascularisation
settings, where oral P2Y12 receptor antagonist may not be adequate such as in PPCI or cardiogenic shock, or similarly
in patients undergoing high-risk intervention such as those with multi-vessel PCI, bifurcation lesion or left main PCI, or those
with early stent thrombosis. The authors however caution that direct head-to-head comparison with newer oral P2Y12 receptor
antagonists (prasugrel and ticagrelor) are lacking, so tailored use to the clinical situation is advised.
In addition to Dual Antiplatelet Therapy (DAPT), use of glycoprotein IIb/IIIa inhibitors, significantly reduced ischemic
complications in patients undergoing PCI, particularly in ACS, but was offset by increased bleeding. In a detailed review of
clinical trials to date, taking into account the availability of the newer P2Y12-receptor inhibitors and increasing use of the radial
approach, Rubboli and Patti propose a very useful algorithm for selective GPI use in a number of settings including stable angina,
ACS and STEMI, as well as for bailout in the event of no-reflow during complicated PCI.
Beyond the initial ACS, there remains an increased risk of recurrent cardiovascular events over the subsequent 30 days,
despite DAPT. A comprehensive review in this issue evaluates trials of additional antithrombotic therapy over-and-above
DAPT. Whilst additional agents such as anticoagulants or PAR-1 antagonists generally significantly increase bleeding, vorapaxar
or low-dose rivaroxaban may reduce ischemic events in high-risk ACS patients and could be considered on a case-bycase
Aradi and co-workers then focus on the timeframe beyond the guideline-recommended 1-year treatment period for DAPT
and explore trials of more prolonged or alternative antiplatelet agents. They conclude that whilst not for allcomers, some patients
with prior MI may benefit from prolonged DAPT, with low-dose ticagrelor, although the increased bleeding risk highlights
the need for risk stratification and individualised treatment.
Since the refinement of PCI techniques, transvascular aortic valve replacement is the most exciting addition to the armamentarium
of treatments offered in the cath lab. In this setting, where peri-operative stroke is a major concern and absence of
guidelines on adjunctive pharmacotherapy, the authors provide a very thorough and balanced overview of available clinical data including, importantly, the lack of evidence for currently employed DAPT regimens. The review highlights the need to
screen for atrial fibrillation, ongoing clinical trials and possible use of non-vitamin K oral anticoagulants.
Controversy also surrounds the optimal management of the sickest cohort of patients in the cardiac cath lab, namely those
with cardiogenic shock. These patients have a very high short-term mortality and the optimal haemodynamic support remains
an issue of contention. Although trials of intra-aortic balloon counter-pulsation have produced neutral results, newer percutaneous
mechanical devices including the Impella device may have an important role. Options for and evidence supporting such
mechanical support devices in these patients are discussed by Bonello and colleagues.
Finally, there appears to be ethnic variation not only in thrombotic risk, but also in response to antithrombotic medications.
In a detailed and comprehensive review, Jeong and colleagues review the data on the efficacy and safety of antithrombotic
medications in East Asian patients with ACS or undergoing PCI. This ethnic group, while relatively under-represented in clinical
trials, appears to have lower risk of thrombosis but greater susceptibility to bleeding, with different pharmacokinetic and
pharmacodynamic response to P2Y12 inhibitors compared to Westerners. The authors propose the concept of future “racetailored
Cardiac surgery is no doubt a challenge for the surgeon, anesthesiologist and intensivist when trying to minimize the damage
that occurs during its performance by the required ischemia and reperfusion. Both mechanisms have been described as cardiac
preconditioning or postconditioning, in order to to diminish the damage of ischemic injury and reperfusion.
There is an initial evidence, at least in cardiac surgery, that total intra-venous anesthesia (usually a propofol-based total intra-
venous anesthesia) is associated to an increased mortality when compared to an anesthetic plan including an halogenated
anesthetics . In our issue, we will try to deepen into the effector mechanisms of this benefit and will also discover mechanism
that could assist in extracorporeal circulation .
The preoperative right ventricular dysfunction has an influence at the postoperative outcome in patients undergoing valve
surgery. Patients with impaired contractility or altered morphology of the right ventricle are exposed to a high perioperative
risk, mainly to changes in ventricle function detected at echocardiographic findings such as TAPSE or right ventricular dilatation.
The studies evaluating the preoperative administration of levosimendan in patients with ventricular dysfunction demonstrated
cardiac benefits, including;  cardiac index (CI),  stroke volume index (SI), and  left ventricular ejection fraction
(LVEF). Levosimendan is a drug that showed improved cardiac function in the immediate postoperative period. Levosimendan
is beneficial if its use was started prior to the start of the surgery and anesthesia, and was more effective than delayed administration.
The opening of KATP channels in the mitochondria has a predominant role in the protection of the myocardium from
ischaemia and reperfusion injury. The opening of the KATP channel offers a reduction in myocardial cell necrosis and apoptosis
induced by ischaemia–reperfusion injury by attenuation of calcium accumulation in the mitochondria and stabilisation of the
mitochondrial inner membrane permeability. It means a treatment with the KATP channel opener levosimendan prior to myocardial
ischaemia will mimic ischaemic preconditioning. Our intention is to assess whether there is an evidence on the effects of
levosimendan in patients who are undergoing cardiovascular surgery at pre and postconditioning cardiac level .
Neurological dysfunction and various measures of cerebral protection in carotid surgery, or in situations of total circulatory
arrest in cardiac surgery, neurological monitoring and different therapeutic strategies that could reduce their perioperative dysfunction,
as well as handling it in the immediate postoperative period become increasingly important. Neurological complications
associated with cardiovascular surgery are relatively common, and generate a large increase in morbidity and mortality.
The main function of the medical team which evaluates and treats patients who require cardiac surgery is therefore, the proper
assessment and prevention of these complications.
The genesis of postsurgical neurological deficits are a functional or morphological suffering of neurons, by factors related to
surgery (embolism or hypoperfusion), on a sometimes already committed suffering chronic cerebral atherosclerosis. In this area
and in the perioperative suffering are added brain enhancers such as hyperthermia, hyperglycemia, and systemic inflammatory
Impact will be focal, multifocal or diffuse depending on the extent of anatomical damage in relation to the magnitude and
duration of noxa, and according to this will also be the clinical characteristics of neurological manifestations. They range from
cerebral infarction, prolonged coma, stupor, convulsions, or a variety of neuropsychiatric disorders manifested by waking late
and psychomotor excitement (encephalopathy), or subtle changes in intellectual function, memory, and behavior (cognitive
Drugs such as corticosteroids, lignocaine, statins, sodium pentothal, ketamine, sedatives or hypnotics, or maneuvers such as
hypothermia have been proposed as possible neurological protectors. We are trying to determine what is the scientific evidence
for each one of therapeutic strategies .
Our intention is to review the following four points so that this can serve as a guide to physicians involved in treating the
 Mechanisms of Cardioprotection of Halogenated Agents during Extracorporeal Circulation in Cardiac Surgery.
 Halogenated and Cardiovascular Surgery: Has Mortality Really Decreased?
 Calcium Sensitizers in Cardiac Surgery (Who, When, How and Why).
 Neurological Protection in Cardiovascular Surgery.
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