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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 5, Number 3, July 2007
Contents
Editorial
Pp. 173-174
Cannabinoids and Cardiovascular Disease: The Outlook
for Clinical Treatments Pp. 175-184
John C. Ashton and Paul F. Smith
[Abstract]
Novel Anti-Arrhythmic Drugs for Atrial Fibrillation
Management Pp. 185-194
Joachim R. Ehrlich, Stanley Nattel and Stefan H. Hohnloser
[Abstract]
Angiogenic Growth Factors in the Treatment of Peripheral
Arterial Disease Pp. 195-209
Dimitrios Mikroulis, Nikolaos Papanas, Efstratios Maltezos
and Georgios Bougioukas
[Abstract]
New Pharmacologic Approaches to Prevent Thromboembolism
in Patients with Atrial Fibrillation Pp. 211-219
Matthias Hammwöhner, Alessandra D’Alessandro,
Oliver Wolfram and Andreas Goette
[Abstract]
Is There a True Beneficial Effect of Statin Therapy
in the Acute Phase of Unstable Angina or Myocardial Infarction?
Pp. 221-225
Luis C.L. Correia
[Abstract]
Beneficial Effects of Statins on Endothelial Dysfunction
and Vascular Stiffness Pp. 227-237
Polychronis Dilaveris, Georgios Giannopoulos, Maria Riga,
Andreas Synetos and Christodoulos Stefanadis
[Abstract]
The Endothelin Axis: A Novel Target for Pharmacotherapy
of Female Malignancies Pp. 239-248
Martin Smollich and Pia Wülfing
[Abstract]
Abstracts
[Back to top]
Editorial:
PCI and Stable Coronary Heart Disease – COURAGE
to Change Our Minds?
[Back to top]
Cannabinoids and Cardiovascular Disease: The Outlook
for Clinical Treatments
John C. Ashton and Paul F. Smith
Cannabinoid drugs exert their effects primarily through activation
of cannabinoid CB1 and CB2 receptors. Both CB1 and CB2 receptors
have been implicated in a number of cardiovascular processes,
including vasodilation, cardiac protection, modulation of
the baroreceptor reflex in the control of systolic blood pressure,
and inhibition of endothelial inflammation and the progress
of atherosclerosis in a murine model. These effects are mainly
mediated through central and peripheral nervous system CB1
receptors, vascular CB1 receptors and immune cell CB2 receptors.
Relevant cellular effects include: the inhibition of neurotransmitter
release in the nucleus tractus solitarius and in peripheral
adrenergic neurons; regulation of NOS activity in vascular
beds; inhibition of vascular smooth muscle cell excitability;
regulation of endothelial cell migration and proliferation;
and effects on immune cell proliferation, activation, and
inflammatory functions.
We review the pre-clinical evidence for beneficial effects
of cannabinoid drugs in a range of vascular and cardiovascular
pathologies. We also discuss the clinically relevant potential
of cannabinoids.
[Back to top]
Novel Anti-Arrhythmic Drugs for Atrial Fibrillation
Management
Joachim R. Ehrlich, Stanley Nattel and Stefan H. Hohnloser
Atrial fibrillation (AF) is a highly prevalent arrhythmia
and responsible for significant morbidity, mortality and health
care cost. Considerable work has been performed to improve
medical options but treatment success still remains suboptimal.
The use of conventional anti-arrhythmic agents has been limited
by potentially fatal ventricular proarrhythmia. Thus, novel
drug targets have been characterised and are currently being
tested in experimental and clinical studies. The atrially
(but not ventricularly) expressed ion channel subunit Kv1.5
(conducting the ultra-rapid delayed rectifier, IKur)
is a prominent candidate. A variety of drugs that inhibit
this current is being evaluated. Human experience with these
agents is limited. Atrial expression of connexin 40 and downregulation
of this protein in AF turn its modulation into a potential
therapeutic approach. The acetylcholine-activated current
(IKACh) is another novel
candidate target for drug therapy. The constitutively active
form of this current is increased in human AF and pharmacological
inhibition might be of therapeutic value. Certain drugs have
IKACh blocking properties,
but as for IKur-blockers
none to date has shown pure selectivity for this current.
This article summarizes relevant aspects of the cellular electrophysiology
of AF and reviews the actions of pharmacological agents presently
available or in development as novel anti-arrhythmic therapy.
[Back to top]
Angiogenic Growth Factors in the Treatment of Peripheral
Arterial Disease
Dimitrios Mikroulis, Nikolaos Papanas, Efstratios Maltezos
and Georgios Bougioukas
Peripheral arterial disease (PAD) remains a major cause of
morbidity. Despite advances in revascularisation procedures
and medical treatment, limb salvage and relief of pain are
still not satisfactory in patients with severe disease. This
has prompted the exploration of alternative modes of treatment
including enhancement of new vessel formation (angiogenesis).
Angiogenic Growth Factors (AGF), mainly Vascular Endothelial
Growth Factor (VEGF), basic Fibroblast Growth Factor (bFGF)
and Hepatocyte Growth Factor (HGF) have emerged as exciting
therapeutic modalities.
Both experimental and clinical studies have demonstrated that
topical (mainly intramuscular) AGF gene therapy results in
improved peripheral vasculature and alleviation of symptoms.
However, most clinical work is limited to small patient series
and the long-term safety and efficacy are still unclear. Clinical
benefit must be balanced against potential untoward effects,
such as tumour growth and atherosclerotic plaque angiogenesis
leading to plaque instability. VEGF is important in the pathogenesis
of diabetic microvascular disease.
Further studies are required before implementation of AGF
therapy in clinical practice.
[Back to top]
New Pharmacologic Approaches to Prevent Thromboembolism
in Patients with Atrial Fibrillation
Matthias Hammwöhner, Alessandra D’Alessandro,
Oliver Wolfram and Andreas Goette
Atrial fibrillation (AF) is associated with a 6 fold increased
risk for ischemic stroke. Observational studies suggest that
one in four to five strokes is due to AF. Depending on the
risk profile of an individual patient, the yearly risk for
ischemic stroke is between 2% and 14%.
AF is accompanied by an increased propensity for atrial clot
formation due to a combination of decreased atrial blood flow,
increased activity of the platelet/plasmatic coagulation system
and prothrombotic changes at the atrial endocardium.
This review summarizes the current guidelines for thromboembolic
prevention in patients with AF. In many cases, continuous
oral anticoagulation therapy (OAT) with vitamin K antagonists
(VitKAs) is indicated if AF is accompanied by more than one
additional risk factor for thromboembolic complications. However,
therapeutic range of VitKAs (Phenprocoumon, Warfarin, and
others), the most commonly used oral anticoagulants, is narrow
and their use requires regular anticoagulation monitoring.
Possibly due to these limitations, about one third of eligible
patients are not treated with VitKAs. Furthermore, in many
treated patients OAT is not well controlled. Thus, in clinical
practice anticoagulation therapy in AF is suboptimal. Therefore,
new and more convenient pharmacologic approaches to prevent
thromboembolism with i.e. direct thrombin inhibitors (DTI),
synthetic polysaccharides (factor Xa Inhibitors), and others
are discussed, and their possible future role in the treatment
of AF is evaluated.
[Back to top]
Is There a True Beneficial Effect of Statin Therapy
in the Acute Phase of Unstable Angina or Myocardial Infarction?
Luis C.L. Correia
It has been claimed that early use of statins in acute coronary
syndromes (ACS) protects patients against recurrent ischemic
events. This protective effect takes place as early as 4 months
after treatment initiation in non-ST elevation ACS, as reported
in the MIRACL trial. Mechanisms such as improvement in endothelial
function and inflammation are possible explanations for this
early effect. These findings have been used to propose statins
as part of the acute phase therapy. However, the use of statins
during hospitalization is an unresolved issue, because there
is a lack of evidence regarding the benefit of initiating
therapy in the acute phase. Most randomized trials included
patients after several days of the index event and did not
report in-hospital outcome.
This review critically discusses the use of statins in ACS
and the level of evidence regarding their beneficial effect
in acute phase treatment.
[Back to top]
Beneficial Effects of Statins on Endothelial Dysfunction
and Vascular Stiffness
Polychronis Dilaveris, Georgios Giannopoulos, Maria Riga,
Andreas Synetos and Christodoulos Stefanadis
Endothelial dysfunction and increased arterial stiffness are
considered independent predictors of cardiovascular risk.
Endothelial dysfunction primarily reflects decreased availability
of nitric oxide, a critical endothelium-derived vasoactive
factor with vasodilatory and anti-atherosclerotic properties.
Techniques for assessing endothelial dysfunction include ultrasonographic
measurement of flow-mediated vasodilatation of the brachial
artery and plethysmographic measurement of forearm blood flow
responses to vasoactive agents. Arterial stiffness can be
assessed using pulse wave analysis to generate measures of
pulse wave velocity, arterial compliance and wave reflection.
It has been demonstrated that the preventive effect of statins
on coronary events is not only attributed to cholesterol-lowering,
but also to various effects on the vascular wall, which include
improved endothelial function as well as antioxidant and anti-inflammatory
activity. Previous studies have reported improvement of arterial
stiffness by the antioxidant and anti-inflammatory effects
of statin therapy in patients with or without hypercholesterolemia.
The present review considers the pathophysiology underlying
endothelial dysfunction and increased arterial stiffness associated
with atherosclerotic disease and the beneficial effects of
statins on these markers of atherosclerosis.
[Back to top]
The Endothelin Axis: A Novel Target for Pharmacotherapy
of Female Malignancies
Martin Smollich and Pia Wülfing
The endothelin axis (ET axis), comprising the three peptides
endothelin (ET)-1, -2, -3 and their receptors ETAR
and ETBR, is expressed in
various cells and tissues. The biologically active ET-1 is
formed by endothelin-converting enzyme (ECE) from inactive
big-ET-1. ET-1 has emerged as an important peptide in a host
of biological functions, including development, cellular proliferation,
apoptosis and angiogenesis, thereby playing an important physiological
and pathophysiological role. As these effects are mediated
by ETAR, activation of ETBR
prevents apoptosis, inhibits ECE expression and mediates the
clearance of ET-1. Emerging data indicate that the ET axis
is involved in tumourigenesis and tumour progression of various
cancers.
Expression of the ET axis has been demonstrated in a wide
range of human tumours. Since most data have been reported
for female malignancies, this review will focus on the role
of the ET axis in cancers of the ovary, the cervix and the
breast. In ovarian cancer, activation of ETAR
by ET-1 is a key mechanism in the cellular signalling network
promoting cancer growth and progression. Similar effects have
been shown for cervical and endometrial cancer. In breast
cancer, ET-1 via ETAR
promotes proliferation and invasion, mediates bone metastases
and predicts unfavourable response to chemotherapy.
The outstanding role of ET-1 and ETAR
in carcinogenesis and tumour progression has led to an extensive
search for interfering agents, resulting in the development
of selective ETAR antagonists
on the one hand and inhibitors of the endothelin-converting
enzyme (ECE) on the other. Targeting the ET axis via
ETAR or ECE blockade seems
to be a promising approach in the treatment of female malignancies.
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