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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 4, Number 3, July 2006
Contents
The Metabolic Syndrome: Revisiting the Concept, the
Diagnosis and the Treatment (Part-I)
Guest Editors: John H. McNeill and Vijay Sharma
Editorial Pp. 173-174
Dyslipidaemia, Hypercoagulability and the Metabolic Syndrome
Pp. 175-183
Anna I. Kakafika, Evagelos N. Liberopoulos, Asterios Karagiannis,
Vasilios G. Athyros and Dimitri P. Mikhailidis
[Abstract]
Definitions of Metabolic Syndrome: Where are We
Now? Pp. 185-197
Stella S. Daskalopoulou, Vassilis G. Athyros, Genovefa
D. Kolovou, Katherine K. Anagnostopoulou and Dimitri P. Mikhailidis
[Abstract]
General Articles
Vascular Effects of Ambient Pollutant Particles and
Metals Pp. 199-203
Yuh-Chin T. Huang and Andrew J. Ghio
[Abstract]
Crucial Role of Interferon-γ
and Stimulated Macrophages in Cardiovascular Disease
Pp. 205-213
Katharina Schroecksnadel, Barbara Frick, Christiana Winkler
and Dietmar Fuchs
[Abstract]
Role of Oxidative Stress in Development of Cardiovascular
Complications in Diabetes Mellitus Pp. 215-227
Mohamed A. Haidara, Hanaa Z. Yasin, Moshira Rateb, Hania
Ammar and Mahmoud A. Zorkani
[Abstract]
Myocardial Contrast Echocardiography: Role in
Clinical Cardiology Pp. 229-235
Girish Dwivedi, Sajad Ahmed Hayat, Rajesh Janardhanan
and Roxy Senior
[Abstract]
Hyperhomocysteinemia in Movement Disorders: Current
Evidence and Hypotheses Pp. 237-243
Stefano Zoccolella, Davide Martino, Giovanni Defazio,
Paolo Lamberti and Paolo Livrea
[Abstract]
Statins for Diabetic Cardiovascular Complications
Pp. 245-251
Sora Ludwig and Garry X. Shen
[Abstract]
Drug Therapies in the Secondary Prevention of
Cardiovascular Diseases: Successes, Shortcomings and Future
Directions Pp. 253-268
Eva Lonn and Jasmine Grewal
[Abstract]
The Molecular Mechanisms of Vascular Restenosis:
Which Genes are Crucial? Pp. 269-275
Jemma Bhoday, Sampath de Silva and Qingbo Xu
[Abstract]
Facing Up the ROS Labyrinth - Where To Go? Pp.
277-289
Armando Rojas, Hector Figueroa, Miguel A. Morales and
Lamberto Re
[Abstract]
Abstracts
[Back to top]
Editorial
We are faced with an alarming epidemic of obesity,
diabetes and cardiovascular disease. For this reason, the
Metabolic Syndrome (MetS) has been receiving a great deal
of attention both from the scientific community and from the
general public. A recent statement from the American Diabetes
Association (ADA) and the European Association for the Study
of Diabetes (EASD) called for the concept of the MetS to be
re-evaluated (1). The MetS serves two purposes: it is a concept
and it is a diagnosis. As a concept, the MetS highlights the
fact that its components tend to cluster together. This has
raised awareness of cardiovascular risk among health care
workers and the general public. It has also provided a conceptual
framework in which that risk can be managed. There is, therefore,
no doubt that the concept has been useful. The main controversy
which surrounds the concept comes down to one key question:
what is required to make a syndrome?
In a syndrome, a number of symptoms, signs and/ or physiological
traits are related to a single underlying cause. In Cushing’s
syndrome, the cause is corticosteroid excess. In the Sleep
Apnea/ Hypopnea syndrome, the underlying cause is intermittent
obstruction of the airway during sleep. Both of these syndromes
have a clear definition. Corticosteroid excess or airway obstruction
may be caused by a wide range of factors, but there is a clear
unifying feature. Furthermore, once the diagnosis of either
syndrome is made, that diagnosis influences the subsequent
investigation and treatment of the patient. When the existence
or usefulness of a syndrome is examined, this is the standard
it is expected to meet. The MetS does not measure up to this
standard partly because the necessary research is still ongoing,
and partly because it is very different in nature from the
syndromes against which it is being judged.
The MetS is an asymptomatic syndrome; its components are all
physiological traits. This immediately makes its existence
as an entity harder to grasp and conclusively prove than,
for example, Cushing’s syndrome. The proposed unifying
feature of its components is insulin resistance, which is
itself a very heterogeneous and complex physiological trait.
Insulin resistance can occur in the context of a far wider
neuroendocrine dysfunction, and can be regarded as a cause,
a consequence, a sustainer and a marker of this dysfunction.
Furthermore, whole body insulin resistance is the collective
result of insulin resistance, which occurs at the cell, tissue
and organ levels. Finally, there are many mechanisms at every
level, by which insulin resistance can occur. Unifying features
of all forms of insulin resistance will doubtlessly be found,
and several such features are currently being defined. However,
when one takes a global look at the intimidatingly large number
of factors, which act either to cause insulin resistance or
mediate its proposed effects, the emerging picture is one
of a highly complex causal network. Within such a network,
interrelated physiological traits will be found to cluster.
However, there is no simple underlying cause, but rather a
causal network. Is this still a syndrome? We believe that
it is, because the clustering of risk factors is related to
a meaningful underlying cause, albeit one which is less straightforward
than the elevated corticosteroid levels in Cushing’s
syndrome.
The usefulness of the Metabolic Syndrome as a diagnosis
requires much further study. There are several proposed definitions
of the MetS accompanied by several confouding questions such
as; Which should be used and in which situations? Which group
of patients should we seek to identify: patients with insulin
resistance or patients with increased cardiovascular risk?
Does a diagnosis of the MetS influence the clinical management?
However, no specific treatment strategy exists at the present
time. Should the MetS be treated as a distinct all-or-nothing
diagnosis, or simply as a conceptual framework? There has
been concern that the use of the MetS as a diagnosis may lead
clinicians to ignore individual risk factors in patients who
do not meet the criteria for diagnosis. There is, to our knowledge,
no evidence that this is the case.
Does the use of the MetS as a diagnosis improve patient outcomes?
This is a key question which has not been adequately addressed.
Does the diagnosis of the MetS change the management of the
patient? There is, at present, no specific treatment strategy
for the MetS, it is not yet clear what is required over and
above the management of the individual risk factors.
The aim of this two-part special issue of Current Vascular
Pharmacology is to provide a broad overview of the experimental
and clinical research, which has sought to answer these important
questions. The MetS, both as a concept and a diagnosis, will
be re-examined. Future directions for research to elucidate
the pathogenesis of the MetS and to determine the clinical
utility of the MetS as a diagnosis will be suggested. Finally,
existing and future treatment strategies for the MetS will
be discussed.
In Part One, Daskapoulou et al. assess and compare
all of the definitions of the MetS, which have been proposed
to date. This review highlights the key conceptual and practical
differences that exist between the current definitions. Should
the MetS be strictly a pre-diabetic state, or can it also
include type 2 diabetes? Should a measure of insulin resistance
be included in the definition? The authors also highlight
the need for specific definitions of the MetS, which can be
applied to specific populations. In particular, there is no
specific definition for children and adolescents. Kakafika
et al. then provide a clinical overview of dyslipidemia
and abnormal hemostasis within the context of the MetS.
We believe that the MetS does exist as a syndrome, and that
the underlying concept is very useful. This special issue
will examine the ways in which the concept has guided our
understanding of cardiovascular risk factors. As long as the
MetS is not viewed as a discrete all-or-nothing diagnosis,
and individual risk factors are treated, the concept is very
useful clinically. The value of the MetS as a diagnosis will
be clearer, once the confusion surrounding its definitions
is resolved and once its impact on patient outcomes and clinical
management is known. We encourage scholarly debate about these
issues. However, to write off the Metabolic Syndrome as a
non-existent non-entity is a premature over-reaction to difficulties,
which will be resolved with time.
REFERENCE
[1] Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome:
time for a critical appraisal: joint statement from the American
Diabetes Association and the European Association for the
Study of Diabetes. Diabetes Care 2005; 28(9): 2289-304.
Dr. Vijay Sharma
Division of Pharmacology and Toxicology
Faculty of Pharmaceutical Sciences
The University of British Columbia
2146 East Mall, Vancouver, V6T 1Z3
Canada
E-mail: vijaysha@interchange.ubc.ca
Dr. John H. McNeill
Division of Pharmacology and Toxicology
Faculty of Pharmaceutical Sciences
The University of British Columbia
2146 East Mall, Vancouver, V6T 1Z3
Canada
E-mail: jmcneill@interchange.ubc.ca
[Back to top]
Dyslipidaemia, Hypercoagulability and
the Metabolic Syndrome
Anna I. Kakafika, Evagelos N. Liberopoulos, Asterios Karagiannis,
Vasilios G. Athyros and Dimitri P. Mikhailidis
The metabolic syndrome is a clustering of risk factors
including central obesity, insulin resistance, dyslipidaemia
and hypertension. This syndrome is associated with increased
risk of cardiovascular disease and is a common early abnormality
in the development of type 2 diabetes. The pathogenesis of
the syndrome has multiple origins. Obesity and sedentary lifestyle
coupled with genetic factors interact to produce the syndrome.
Here, we consider two components of the metabolic syndrome,
dyslipidaemia and hypercoagulability.
[Back to top]
Definitions of Metabolic Syndrome: Where
are We Now?
Stella S. Daskalopoulou, Vassilis G. Athyros, Genovefa
D. Kolovou, Katherine K. Anagnostopoulou and Dimitri P. Mikhailidis
The metabolic syndrome (MetS) is a cluster of metabolic
abnormalities including abdominal obesity, glucose intolerance,
hypertension and dyslipidaemia and is associated with an increased
risk of vascular events. Since the initial description of
the MetS, several expert groups produced different definitions.
This variability led to confusion and absence of comparability
between studies.
Although there is agreement that the MetS is a major public
health challenge worldwide and consistent evidence stresses
the need for intervention, the definition of the syndrome
remains a matter of debate.
This review considers the different definitions of the MetS.
These include those proposed by the World Health Organisation,
the European Group for the Study of Insulin Resistance, the
National Cholesterol Education Program Adult Treatment Panel
III, the American College of Endocrinology and American Association
of Clinical Endocrinologists and the latest International
Diabetes Federation definition which includes ethnic-specific
waist circumference cut-off points. These definitions share
several features but also include important differences; all
have limitations. Selected (after a Med-line search) studies
comparing the different definitions are also considered.
There is a need for a standardised definition of the MetS.
Furthermore, a definition tailored for children and adolescents
is essential. Prospective long-term studies are needed to
validate the prognostic power of these definitions. As new
information becomes available the definition of the MetS might
be further modified.
[Back to top]
Vascular Effects of Ambient Pollutant Particles
and Metals
Yuh-Chin T. Huang and Andrew J. Ghio
Exposure to ambient pollutant particle (APP) is associated
with increased cardiovascular morbidity and mortality. Recent
evidence indicates that APP-induced vasoconstriction may be
an important mechanism. APP constricts systemic arteries and
increases blood pressure in human. APP decreases the diameter
of pulmonary arterioles in animals. Intratracheal instillation
of APP increases pulmonary artery resistance in isolated buffer-perfused
lungs, and APP constricts isolated arterial rings. APP-induced
vasoconstriction may be secondary to the release of inflammatory
mediators from lung cells, which then activate vascular endothelial
and smooth muscle cells. The vasoconstriction may also be
caused by alterations in autonomic nervous system balance.
Some soluble metals (e.g., vanadium) can produce acute vasoconstriction
in in vitro and in vivo systems, and contribute
to the systemic health effects of APP since they can more
easily permeate the alveolar-capillary membrane than the whole
particle. Both APP and its associated metals have been shown
to enhance the release of endothelin 1 and reactive oxygen
species, activate epithelial growth factor receptor and mitogen-activated
protein kinases, and inhibit nitric oxide vasodilator activity.
The vasoactive properties of APP and metals raised the possibility
that patients with vascular diseases may be more susceptible
to APP-induced adverse health effects, and that people who
are regularly exposed to high amount of metals, e.g., vanadium
contained in certain dietary and muscle-building regimens
or in the air of boiler making plants, may have increased
risk for vascular diseases. Understanding how metals induce
vasoconstriction may lead to the development of novel vasodilator
therapies for vascular diseases.
[Back to top]
Crucial Role of Interferon-γ
and Stimulated Macrophages in Cardiovascular Disease
Katharina Schroecksnadel, Barbara Frick, Christiana Winkler
and Dietmar Fuchs
Inflammation and immune activation are crucially involved
in the pathogenesis of atherosclerosis and cardiovascular
disease. Accordingly, markers of inflammation such as fibrinogen,
ferritin, C-reactive protein or neopterin are found in patients
with vascular diseases, correlating strongly with the extent
of disease and predicting disease progression. Neopterin formation
by human monocyte-derived macrophages and dendritic cells
is induced by the pro-inflammatory cytokine interferon-γ,
which is released by activated T-lymphocytes. Human macrophages
are centrally involved in plaque formation, and interferon-γ
and macrophages are also of importance in the development
of oxidative stress for antimicrobial and antitumoural defence
within the cell-mediated immune response. Interferon-γ
also stimulates the enzyme indoleamine-2,3-dioxygenase, which
degrades tryptophan to kynurenine. Again, macrophages are
the most important cell type executing this enzyme reaction,
but also other cells like dendritic cells, endothelial cells
or fibroblasts can contribute to the depletion of tryptophan.
Likewise, enhanced tryptophan degradation was reported in
patients with coronary heart disease and was found to correlate
with enhanced neopterin formation.
In chronic diseases such as in cardiovascular disease, biochemical
reactions induced by interferon-γ
may have detrimental consequences for host cells. In concert
with other pro-inflammatory cytokines, interferon-γ
is the most important trigger for the formation and release
of reactive oxygen species (ROS). Chronic ROS-production leads
to the depletion of anti-oxidants like vitamin C and E and
glutathione, with a consequence that oxidative stress develope.
Oxidative stress plays a major role in the atherogenesis and
progression of cardiovascular disease, and it may also account
for the irreversible oxidation of other oxidation-sensitive
substances like B-vitamins (e.g. folic acid and B12). They
are essential cofactors in homocysteine-methionine metabolism.
Associations between moderate hyperhomocysteinaemia and cellular
immune activation are found in several diseases including
coronary heart disease, and data indicate that hyperhomocysteinaemia
may develop as a consequence of immune activation. Homocysteine
accumulation in the blood is established as an independent
risk factor for cardiovascular disease. Homocysteine itself
has the capacity to further enhance oxidative stress.
Interferon-γ
appears to be a central player in atherogenesis and in the
development and progression of cardiovascular disease. Anti-inflammatory
and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory
drugs or statins) may among other consequences, also contribute
to a slow-down of the adverse effects of interferon-γ.
[Back to top]
Role of Oxidative Stress in Development of
Cardiovascular Complications in Diabetes Mellitus
Mohamed A. Haidara, Hanaa Z. Yasin, Moshira Rateb, Hania
Ammar and Mahmoud A. Zorkani
Diabetes represents a serious risk factor for the development
of cardiovascular problems such as coronary heart disease,
peripheral arterial disease, hypertension, stroke, cardiomyopathy,
nephropathy and retinopathy. Identifying the pathogenesis
of this increased risk provides a basis for secondary intervention
to reduce morbidity and mortality in diabetic patients. Hyperglycemia
and protein glycation, increased inflammation, a prothrombotic
state and endothelial dysfunction have all been implicated
as possible mechanisms for such complications.
A linking element between many of these phenomena could possibly
be, among other factors, increased production of reactive
oxygen species.
Vascular endothelial cells have several physiological actions
that are essential for the normal function of the cardiovascular
system. These include the production of nitric oxide (NO),
which regulates vasodilatation, anticoagulation, leukocyte
adhesion, smooth muscle proliferation and the antioxidative
capacity of endothelial cells. However, under conditions of
hyperglycemia, excessive amounts of superoxide radicals are
produced inside vascular cells and this can interfere with
NO production leading to the possible complications.
This article aims at reviewing the links between reactive
oxygen species, diabetes and vascular disease and whether
or not antioxidants can alter the course of vascular complications
in diabetic patients and animal models. A possible beneficial
effect of antioxidants might present a new addition to the
range of secondary preventive measures used in diabetic patients.
[Back to top]
Myocardial Contrast Echocardiography: Role
in Clinical Cardiology
Girish Dwivedi, Sajad Ahmed Hayat, Rajesh Janardhanan
and Roxy Senior
Recent updates in the field of echocardiography have resulted
in improvements in both image quality and techniques allowing
echocardiography to maintain its position as the primary non-invasive
imaging modality. In particular, the development of new ultrasound
contrast agents and imaging techniques have now made possible
the assessment of myocardial perfusion. Myocardial contrast
echocardiography utilises acoustically active gas filled microspheres
(microbubbles), which have rheology similar to that of red
blood cells. The detection of myocardial perfusion during
echocardiographic examinations permits simultaneous assessment
of global and regional myocardial structure, function, and
perfusion, enabling the optimal non-invasive assessment of
coronary artery disease. Myocardial contrast echocardiography
is equally adept in assessing chronic coronary artery disease
as well as acute coronary syndromes. Furthermore, its use
is not limited solely to diagnostic assessment. Preliminary
evidence suggests that targeted microbubbles may be useful
in enhancing delivery of genes / drugs and in clot lysis.
[Back to top]
Hyperhomocysteinemia in Movement Disorders:
Current Evidence and Hypotheses
Stefano Zoccolella, Davide Martino, Giovanni Defazio,
Paolo Lamberti and Paolo Livrea
Elevated plasma levels of homocysteine (Hcy) are a risk
factor for systemic vascular diseases, stroke and vascular
dementia. In recent years, increasing Hcy levels have been
detected in neurological disorders that are not vascular in
origin including Alzheimer’s Disease and movement disorders
(MD) such as idiopathic Parkinson’s Disease (PD), Hunt-ington’s
Disease (HD) and primary dystonia. Hyperhomocysteinemia (HHcy)
in PD results from L-Dopa administration and its O-methylation
dependent from catechol-O-methyltransferase and may be implicated
in the development of motor complications and non-motor symptoms,
such as dementia. In a recent study, HHcy has been evidenced
in HD patients, compared to controls. Because mutated Huntington
protein influences Hcy metabolism by modulating cystathionine-β-synthase
activity, Hcy could represent a biological marker of neurodegeneration
and could explain the leading role of cardiovascular and cerebrovascular
diseases as causes of death in HD. Finally, several cases
of homocystinuria associated with dystonia, and some recent
reports of elevated Hcy in patients with primary adult onset
dystonia have been published. Increased Hcy plasma levels
may have important implications in patients affected by these
basal ganglia disturbances, by exerting neurotoxic effects,
contributing to neurotransmitter imbalance in motor circuits,
and increasing the risk for vascular insults and cognitive
dysfunctions.
[Back to top]
Statins for Diabetic Cardiovascular Complications
Sora Ludwig and Garry X. Shen
The prevalence of diabetes mellitus (DM), particularly
Type 2 DM, has rapidly increased in industrialized and many
developing countries. The predominant cause of death in diabetic
patients is vascular complications. Dyslipidemia and hypercholesterolemia
are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA
reductase inhibitors (statins) were designed for lowering
cholesterol synthesis. Landmark clinical trials indicated
that statins effectively reduced cardiac death and events
in patients with coronary artery disease or DM. The benefits
of statins on the prevention of vascular events were independent
from age, sex or baseline lipid levels in diabetic patients.
Statins not only prevent atherosclerotic macrovascular complications,
but also postpone the development of microvascular complications
of DM, such as nephropathy and retinopathy. The non-cholesterol
lowering or pleiotropic effects of statins have attracted
vast attention. Results from experimental and clinical studies
suggest that statins may attenuate inflammation, oxidative
stress, coagulation, platelet aggregation, and improve insulin
resistance, fibrinolysis and endothelial functions and help
to prevent thrombosis, restenosis or organ transplantation
rejection. Statins may affect the intracellular prenylation
of proteins, which modulate the activity of small-GTP binding
proteins. This may be an underlying mechanism for some pleiotropic
effects of statins. Statins have an excellent safety profile
and seldom cause adverse effects. Increasing evidence suggests
that statins are the current treatment of choice to prevent
vascular complications in diabetic patients with hypercholesterolemia.
[Back to top]
Drug Therapies in the Secondary Prevention
of Cardiovascular Diseases: Successes, Shortcomings and Future
Directions
Eva Lonn and Jasmine Grewal
Cardiovascular diseases are the major cause of death
and a significant cause of disability in the Western world
and more recently threaten to pose an increasing health burden
on developing nations. People with pre-existent vascular disease
are those at highest risk for adverse cardiovascular outcomes
and require aggressive secondary preventive therapies. Large
strides have been made in the development of pharmacologic
agents that intervene on various pathways implicated in atherogenesis,
thus offering the ability to greatly impact on disease progression
and to prevent events. Compelling data derived primarily from
randomized controlled trials have shown the benefits of aspirin
(or antiplatelet agents) and angiotensin converting enzyme
(ACE) inhibitors (A), beta-blockers and blood pressure (B)
and cholesterol-lowering drugs (C), particularly statins,
in preventing recurrent events and improving survival. Taken
together these data are the foundation for the simple, but
important advice for secondary prevention – the ABCs.
In addition, the evidence for the central role of lifestyle
factors as determinants of risk has lead to increased efforts
towards developing interventions aimed at modifying lifestyle
patterns. Today, the biggest challenge remains in the implementation
of proven effective therapies. Our focus should turn to educating
physicians and patients alike regarding available therapies
and their indications. In addition systematic, sustainable
and globally applicable approaches to the secondary prevention
of cardiovascular diseases need to be developed to truly realize
the vast potential benefits of existing therapies.
[Back to top]
The Molecular Mechanisms of Vascular Restenosis:
Which Genes are Crucial?
Jemma Bhoday, Sampath de Silva and Qingbo Xu
Many patients with coronary heart disease undergo percutaneous
transluminal coronary angioplasty (PTCA) to improve myocardial
tissue perfusion. However, a major complication after revascularisation
procedures is restenosis of the injured artery. The molecular
mechanism involved is not fully elucidated and no successful
treatment is currently available.
Animal models are preliminary tools that can help improve
our understanding of the pathogenesis and treatment of restenosis
in humans. Attracted by well-defined genetic systems, a number
of investigators began to use the mouse as an experimental
system for restenosis research. They demonstrated that several
stages involved in this process include thrombus formation,
inflammatory cell infiltration and smooth muscle cell (SMC)
accumulation to form neointimal lesions. By using transgenic
and knockout mice a number of genes related to these processes
have been found to play a major role in mediating lesion formation,
e.g. the plasminogen system, matrix metalloproteinases (MMP),
adhesion molecules, cytokines and signal transducers.
This review will not attempt to cover all aspects of related
genes or molecules, but will rather focus on several groups
of genes, by which the major progress in understanding the
mechanisms of the disease has been made. The information obtained
by using animal models could be essential for a better understanding
of the pathogenesis of restenosis in humans and to provide
a basis for therapeutic intervention.
[Back to top]
Facing Up the ROS Labyrinth - Where To Go?
Armando Rojas, Hector Figueroa, Miguel A. Morales and
Lamberto Re
Evidence indicates that oxidative stress refers to a
condition where cells are subjected to excessive levels of
reactive oxygen species (ROS). Overall vascular function is
dependent upon a fine balance between oxidant and antioxidant
mechanisms which is required, at least in part, for proper
functioning of the endothelium. Considerable experimental
and clinical data indicate that the intracellular oxidant
milieu is also involved in several redox-sensitive cellular
signaling pathways, such as ion transport systems, protein
phosphorylation, and gene expression and thus also plays important
roles as modulator of vascular cell function, such as cell
growth, apoptosis, migration, angiogenesis and cell adhesion.
Over-production of ROS under pathophysiologic conditions is
integral in the development of vascular disease. This fact
stimulated an intensive search of new pharmacological approaches
to improve vascular hemeostasis and, particularly those intended
to decrease oxidative stress or augment the antioxidant defense
mechanisms.
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