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Current
Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 6, Number 1, January 2008
Contents
Fish Oil Fatty Acids as Cardiovascular Drugs Pp.
1-12
Alexander Leaf, Jing X. Kang and Yong-Fu Xiao
[Abstract]
Familial Combined Hyperlipidaemia: Under - Defined
and Under - Diagnosed? Pp. 13-22
Anthony S. Wierzbicki, Colin A. Gram, Ian S. Young and
D. Paul Nicholls
[Abstract]
Advances in Treating the Ischaemic Diabetic Foot
Pp. 23-28
Nikolaos Papanas and Efstratios Maltezos
[Abstract]
Platelet GPIIb/IIIa Receptor Antagonists in Human
Ischemic Brain Disease Pp. 29-36
Rüdiger J. Seitz and Mario Siebler
[Abstract]
Mechanisms of Intimal Hyperplasia Learned from a Murine
Carotid Artery Ligation Model Pp. 37-43
Le-Ning Zhang, John F. Parkinson, Christopher Haskell
and Yi-Xin Wang
[Abstract]
Advanced Glycation and ROS: A Link between Diabetes
and Heart Failure Pp. 44-51
Armando Rojas, Enrique Mercadal, Hector Figueroa and Miguel
A. Morales
[Abstract]
Endothelial Dysfunction, Impaired Endogenous Platelet
Inhibition and Platelet Activation in Diabetes and Atherosclerosis
Pp. 52-60
Andreas Schäfer and Johann Bauersachs
[Abstract]
Randomized Clinical Stroke Trials in 2006
Pp. 61-66
Meheroz H. Rabadi and John P. Blass
[Abstract]
Pharmacological Regulation of Dyslipoproteinaemia
in Insulin Resistant States Pp. 67-77
Dick C. Chan and Gerald F. Watts
[Abstract]
Abstracts
[Back to top]
Fish Oil Fatty Acids as Cardiovascular Drugs
Alexander Leaf, Jing X. Kang and Yong-Fu Xiao
Starting in the 1970s the hypothesis that the low mortality
from coronary heart disease among the Greenland Eskimos was
due to their high consumption of n-3 fish oil fatty acids,
initiated many studies to find if the n-3 polyunsaturated
fatty acids in fish oils (PUFAs) could prevent cardiac atherosclerosis.
To date this possibility has not achieved clinical recognition.
The recent literature shows an increase of intervention studies
to learn if the fish oil fatty acids can reduce mortality
from sudden cardiac death, and the mechanism(s) of such a
protective effect. Indeed the most definite beneficial cardiac
action of these n-3 PUFAs seems now to be their ability in
the short term to prevent sudden cardiac death. It is apparent
that over long periods of time the n-3 fish oil fatty acids
also prevent atherosclerosis.
Definition of the fatty acids to which I will be referring
in the text:
n-6 (omega-6) polyunsaturated fatty acids; linoleic acid (18:2n-6,
LA); arachidonic acid (C20:4n-6,
AA).
n-3 (omega-3) fatty acids; α-linolenic
acid (18:3n-3, ALA); eicosapentaenoic
acid (20:5n-3, EPA); docosahexaenoic
acid (C22:6n-3, DHA).
The bold, underlined abbreviation will appear in the text
to identify the fatty acid being discussed.
[Back to top]
Familial Combined Hyperlipidaemia: Under - Defined and Under
- Diagnosed?
Anthony S. Wierzbicki, Colin A. Gram, Ian S. Young and
D. Paul Nicholls
Familial combined hyperlipidaemia (FCH) was identified
in early genetic studies of populations as a dominant condition
associated with mixed hyperlipidaemia and early onset coronary
heart disease. Later studies extended the phenotype and noted
that this genetic hyperlipidaemia was sensitive to environmental
effects. This article reviews the definitions, animal models
and genetics of FCH.
In contrast to familial hypercholesterolaemia, which is caused
by mutations in a limited number of affected genes, the genetics
of FCH have remained obscure and very few definite candidate
genes have been identified. A strong role for the apoA-I,
A-IV, A-V, C-III cluster on chromosome 11 was identified early
on and multiple associations have been found to hyperlipidaemia
in this region and more strongly to adjacent sections of the
chromosome. More recently quantitative trait mapping has identified
a number of candidate genes including upstream transcription
factor -1 (USF-1) on 1 q21 and CD-36 on chromosome 4. Of these
the strongest evidence, based on 4 analyses, links the lipid
components of FCH to intronic variants in the USF-1 gene on
chromosome 1q21-23. Unfortunately USF-1 yet fails to show
clear associations with diabetes and the metabolic syndrome
which co-map to this region and are also associated with mixed
hyperlipidaemia. Large scale validation of USF-1 variants
in other populations is still awaited.
It is likely that FCH is a heterogeneous condition, that is
subject to wide-scale environmental confounding from common
traits such as obesity and the metabolic syndrome, and that
the resolution of its genetics is going to prove a severe
challenge.
[Back to top]
Advances in Treating the Ischaemic Diabetic Foot
Nikolaos Papanas and Efstratios Maltezos
The diabetic foot remains a major cause of morbidity
worldwide. Ischaemia due to peripheral arterial disease significantly
contributes to its pathogenesis and natural history. Increased
revascularisation has been decisive in improving outcomes.
However, there is still a need for further improvement. Advances
in the treatment of ischaemia in the diabetic foot include
therapeutic angiogenesis, stem cell therapy and miscellaneous
modalities. Angiogenesis has yielded encouraging results in
the treatment of peripheral arterial disease, but it has not
been studied enough in patients with diabetes. Choice of patients,
reliable study endpoints, as well as safety of growth factors
in diabetic patients, who have an excess risk of widespread
vascular disease, need to be addressed more convincingly.
Similar improvement is required in the other emerging therapeutic
options. From a practical point of view, until novel modalities
are available, increased vigilance and prompt aggressive revascularisation
are indispensable to reduce the rate of amputations.
[Back to top]
Platelet GPIIb/IIIa Receptor Antagonists in Human Ischemic
Brain Disease
Rüdiger J. Seitz and Mario Siebler
The goal of acute stroke therapy is to salvage brain
tissue by rapid cerebral artery recanalization to improve
microcirculation. A major drawback of fibrinolysis is the
activation of platelets leading to a high rate of re-occlusion.
Antagonists of the platelet GPIIb/IIIa-receptor inhibit the
binding of fibrinogen to platelets counteracting secondary
thrombus formation. Also, they were shown to suppress thrombembolus
formation and to limit lesion development in cerebral ischemia.
We review the literature concerning the use of intravenously
administered GPIIb/IIIa-receptor antagonists abciximab, eptifibatide
and tirofiban for the treatment of patients with acute ischemic
brain infarction. In multicenter, prospective, randomized
and placebo-controlled trials abciximab had a higher cerebral
bleeding risk, while tirofiban did not increase hemorrhage.
When combined with fibrinolysis, abciximab and tirofiban were
found to improve cerebral artery recanalization and tissue
reperfusion resulting in reduced infarct volumes and improved
neurological outcome. Thus, GPIIb/IIIa-receptor antagonists
have a great potential for the treatment of acute stroke.
[Back to top]
Mechanisms of Intimal Hyperplasia Learned from a Murine Carotid
Artery Ligation Model
Le-Ning Zhang, John F. Parkinson, Christopher Haskell
and Yi-Xin Wang
The murine carotid artery ligation (CAL) model has been
widely used in the research of intimal hyperplasia, a major
pathological process in vascular diseases, such as atherosclerosis
and restenosis after angioplasty. Using a variety of gene
knockout or transgenic mice and different pharmacological
interventions, these studies have yielded significant new
findings that contribute not only to unraveling the basic
molecular mechanisms involved in the pathogenesis of intimal
hyperplasia, but also to the identification of novel targets
for intervention of these diseases. The current review outlines
the findings derived from the murine CAL model, including
studies run by the authors, covering the impacts of hyperlipidemia,
pro-inflammatory factors, endothelial dysfunction, protease
activity and growth mediators on neointimal hyperplasia.
[Back to top]
Advanced Glycation and ROS: A Link between Diabetes and Heart
Failure
Armando Rojas, Enrique Mercadal, Hector Figueroa and Miguel
A. Morales
Despite many advances achieved to date, heart failure
(HF) remains a leading cause of morbidity and mortality. There
is a widely-accepted consensus that HF and diabetes are strongly
linked by at least 3 mechanisms: associated comorbidities,
coronary atherosclerosis or a specific diabetic cardiomiopathy.
For the last 2 mechanisms, advanced glycation end-products
may contribute to trigger key processes relevant to HF by
affecting cardiac function through cross-linking or receptor
engagement.
This review focuses on the main effects of advanced glycation
end-products on cardiomyocytes and endothelial cell function.
Some pharmacological approaches are also discussed.
[Back to top]
Endothelial Dysfunction, Impaired Endogenous Platelet Inhibition
and Platelet Activation in Diabetes an Atherosclerosis
Andreas Schäfer and Johann Bauersachs
Platelet activation induces rapid thrombus formation
at a ruptured atherosclerotic plaque leading to acute vessel
occlusion and a fatal or non-fatal cardiovascular event. More
recent evidence suggests that activated platelets play an
additional central role during the initiation of atherosclerosis,
essentially facilitating leukocyte adhesion and recruitment.
Endothelial dysfunction is a common and early feature of cardiovascular
diseases characterized by reduced bioavailability of prostacyclin
and nitric oxide (NO). Subsequently impaired endogenous platelet
inhibition causes platelet activation in pre-atherosclerotic
vascular disease resulting in enhanced platelet susceptibility
to agonists released from the inflamed endothelium. Platelet
adhesion to inflammatory, dysfunctional endothelium precedes
leukocyte adhesion. Indeed, adherent activated platelets are
mandatory for leukocyte recruitment in the early phases of
atherosclerosis under arterial flow conditions. Increased
expression of chemokines in atherosclerotic plaques and the
inflamed endothelium initiates and facilitates pro-inflammatory
processes in leukocytes and the vascular wall. Apart from
their chemotactic properties, some chemokines such as fractalkine
contribute to platelet activation. Moreover, fractalkine induces
leukocyte recruitment to inflamed endothelial cells under
arterial flow by activating adherent platelets.
An aggressive form of atherosclerosis is found in patients
with diabetes. Since diabetes is currently considered as a
risk equivalent for coronary artery disease, the interaction
between oxidative stress, endothelial dysfunction, impaired
endogenous platelet inhibition and platelet activation is
discussed in the light of diabetes. Defective regulation of
platelet activation/aggregation is a predominant cause for
arterial thrombosis, the major complication of atherosclerosis
triggering myocardial infarction and stroke.
[Back to top]
Randomized Clinical Stroke Trials in 2006
Meheroz H. Rabadi and John P. Blass
This article reviews randomized control trials (RCT’s)
published in 2006 of various medications evaluated for stroke
patients. These trials were primarily efficacy studies. These
included aggrenox (an antiplatelet agent), magnesium (to treat
arterial spasm after an aneurysmal subarachnoid hemorrhage),
NXY (a free radical trapping agent) and albumin which were
both tested as a neuroprotectant, amphetamine (to aid motor
recovery), fluoxetine (an anti-depressant and anxiolytic)
and low molecular weight heparin (for prevention of deep vein
thrombosis post-stroke).
[Back to top]
Pharmacological Regulation of Dyslipoproteinaemia in Insulin
Resistant States
Dick C. Chan and Gerald F. Watts
Dyslipidaemia is a common and consistent abnormality
in insulin resistant subjects with obesity and type 2 diabetes
mellitus associated with increased risk of cardiovascular
disease. Lipoprotein metabolism is complex and abnormal plasma
concentrations can result from alterations in the rates of
production and/or catabolism of diverse lipoprotein particles.
Our understandings of the dysregulation and therapeutic regulation
of lipoprotein transport in insulin resistant states has relied
on the application of advances in stable isotope and modelling
methods. Dysregulation of lipoprotein metabolism in these
circumstances may be caused by a combination of overproduction
of VLDL apolipoprotein (apoB) B-100 and VLDL-apoC-III, decreased
catabolism of apoB-containing particles, and increased catabolism
of HDL apoA-I particles. These abnormalities may be consequent
on a global metabolic effect of insulin resistance and accumulation
of visceral fat. Several pharmacological treatments, such
as statins, fibrates or fish oil can correct the dyslipidaemia
by diverse kinetic mechanisms of action, including decreased
secretion of apoB and apoC-III, and increased catabolism of
apoB, as well as increased secretion and decreased catabolism
of apoA-I. Newer agents, including insulin sensitizers, cholesterol
absorption inhibitors, CETP inhibitors, peroxisome proliferator-activated
receptor-delta agonists and endocannabinoid-1 receptor blockers,
have also been shown to improve plasma lipid and lipoprotein
abnormalities in insulin resistant states; their mechanisms
of action are at present being investigated. Rimonabant is
the endocannabinoid receptor blocker shown to decrease cardiometabolic
risk in insulin resistant subjects. The complementary mechanisms
of action of different agents support the use of combination
regimens in treating dyslipoproteinaemia in subjects with
central obesity and type 2 diabetes.
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