Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 6, Number 4, December 2006
Contents
Vascular C-Reactive Protein in the Pathogenesis
of Coronary Artery Disease: Role of Vascular Inflammation
and Oxidative Stress Pp. 227-231
Nobutaka Inoue
[Abstract]
Evaluation and Management of Atrial Fibrillation
Pp. 233-244
Sheharyar Ali, Mauricio Hong, Eduardo S. Antezano and
Iqwal Mangat
[Abstract]
An Update on Clinical and Pharmacological Aspects
of Drug Eluting Stents Pp. 245-255
Rafik R. Anis, Karl R. Karsch and Martin Oberhoff
[Abstract]
Carvedilol: Just Another Beta-Blocker or a Powerful
Cardioprotector? Pp. 257-266
R.S. Carreira, P. Monteiro, L.M. Gonçalves and
L.A. Providência
[Abstract]
Novel Insights Into Lp(a) Physiology and Pathogenicity:
More Questions Than Answers? Pp. 267-278
Marlys L. Koschinsky
[Abstract]
Anti-Inflammatory Effects of Different Drugs/Agents
with Antioxidant Property on Endothelial Expression of Adhesion
Molecules Pp. 279-304
Yung-Hsiang Chen, Shing-Jong Lin, Yuh-Lien Chen, Po-Len
Liu and Jaw-Wen Chen
[Abstract]
Abstracts
[Back to top]
Vascular C-Reactive Protein in the Pathogenesis of Coronary
Artery Disease: Role of Vascular Inflammation and Oxidative
Stress
Nobutaka Inoue
Atherosclerosis is considered to be a chronic inflammatory
disease. Vascular inflammation occurs in response to injury
induced by various stimuli, such as oxidative stress, shear
stress, infection, and so on. This concept is supported by
the recent clinical findings that C-reactive protein (CRP)
is an independent risk factor for coronary heart disease.
CRP, which was originally identified as a protein that could
precipitate the C-polysaccharide of pneumococcal cell walls,
has been widely used as a clinical marker of the state of
inflammation, since its production by hepatocytes increases
during the acute phase of the inflammatory response. Recent
investigations have provided two new concepts for the research
field of CRP, namely, its extra-hepatic production and its
potent biological activities such as the induction of adhesion
molecules and chemokines. Recently, we demonstrated that smooth
muscle cells and macrophages in coronary arteries expressed
CRP protein and mRNA, as evaluated using coronary specimens
of coronary artery disease (CAD) patients obtained by atherectomy.
The expression of vascular CRP was closely associated with
NAD(P)H oxidase, an important enzymatic origin of reactive
oxygen species (ROS) in vessel walls. Furthermore, CRP directly
up-regulated NAD(P)H oxidase p22phox and enhanced
ROS generation in cultured coronary artery smooth muscle cells.
Thus, vascular CRP is likely to be a direct participant in
vascular inflammation and lesion formation via its
potent biological effects. Since lysophos-phatidylcholine,
a major atherogenic lipid of oxidized LDL, was reported to
activate vascular NAD(P)H oxidase, we speculate that there
is a vicious circle consisting of vascular NAD(P)H oxidase,
ROS and oxidized LDL. Since phagocytic NAD(P)H oxidase is
at the first line of the host defense system, it is important
to selectively suppress vascular NAD(P)H oxidase in the localized
inflammatory lesions in therapeutic strategies for CAD. In
this review, we will discuss the roles of vascular CRP and
NAD(P)H oxidase in the pathogenesis of CAD from the viewpoint
of oxidative stress.
[Back to top]
Evaluation and Management of Atrial Fibrillation
Sheharyar Ali, Mauricio Hong, Eduardo S. Antezano and
Iqwal Mangat
Atrial fibrillation (AF) is the most common clinically
encountered arrhythmia affecting 0.4% of the general population.
Its prevalence increases with age, affecting more than 6%
of people over 80 years of age. The annual risk of ischemic
stroke in patients with lone AF is approximately 1.3%. This
annual risk increases up to 10% -12% in patients with a prior
stroke or transient ischemic attack. Randomized clinical trials
(RCT) comparing adjusted-dose oral anticoagulation and placebo
showed a risk reduction of 61% (95% CI 47% to 71%). The absolute
risk reduction for stroke with oral anticoagulants is about
3% per year. Aspirin has been shown in meta-analyses to have
on average a 20-25% relative risk reduction, and is inferior
to oral anticoagulants.
In high risk patients with AF warfarin is a class I ACC/AHA
indication unless there is a contraindication for anticoagulation.
Unfortunately, this therapy requires frequent monitoring with
blood samples and the interaction with food and several medications
makes its use difficult and sometimes unreliable. It requires
strict patient compliance and its use is also linked to potentially
serious bleeding complications. In clinical practice, less
than 60% of patients who do not have contraindications to
oral anticoagulation are actually receiving them. Additionally,
of those that receive oral anticoagulation, less than 50%
are consistently within therapeutic targets. As such, the
“real world” efficacy of a strategy towards prescribing
oral anticoagulants is likely significantly lower than that
demonstrated in clinical trials. As such, the need to discover
other methods of anticoagulation with oral bioavailability,
predictable pharmacokinetics, and minimal interactions with
diet and other pharmacological agents is imperative.
Low molecular weight heparin has a more predictable bioavailability
and a longer half-life, but its subcutaneous mode of administration
and long-term risks, in particular, osteoporosis makes the
chronic use of this medication non-feasible. Antiplatelet
agents such as clopidogrel have proven efficacy and superiority
compared to aspirin to prevent systemic vascular events in
at-risk patient populations, but currently they do not play
an important role in the prevention of AF related thromboembolic
events. The ACTIVE study is a randomized trial comparing the
combination of clopidogrel and aspirin therapy to oral anticoagulation
with warfarin in patients with AF, and was unfortunately terminated
prematurely by the data safety and monitoring board because
of increased events in the antiplatelet arm.
Direct thrombin inhibitors, such as ximelagatran, may be as
effective as warfarin for stroke-risk reduction in patients
with AF. No anticoagulation monitoring is needed and it has
excellent bioavailability, with a twice-daily oral dose. Elevation
of liver enzymes was an initial concern regarding the use
of this new drug, which is not available for general use.
Ongoing pharmacological research and future clinical trials
may one day leave the “warfarin days” behind.
Unfortunately, the new therapies that are being tested seem
to be at least several years away from being available on
a widespread basis.
In this review, we discuss the underlying pathophysiology
of AF and stroke. We also provide a comprehensive discussion
regarding various available therapies to treat AF.
[Back to top]
An Update on Clinical and Pharmacological Aspects
of Drug Eluting Stents
Rafik R. Anis, Karl R. Karsch and Martin Oberhoff
The introduction of stents to clinical practice was the
major breakthrough in the field of percutaneous coronary intervention.
The introduction of stents was associated with two serious
complications, the first was increase in subacute thrombosis
within the first 30 days of stent implantation later controlled
with the use of high pressure inflation and dual antiplatelet
therapy, the second was the phenomenon of in-stent restenosis
that was primarily caused by smooth muscle proliferation.
While coronary stenting eliminates elastic recoil, it is unable
to inhibit excessive neointimal formation. Stents were associated
with an increase of neointimal formation compared to balloon
angioplasty as a result of excessive injury to the vessel
wall and the inflammatory process from interaction of metal
with vessel wall. Local delivery of the potential agents for
inhibition of neointimal formation to the site of the lesion
was considered the desired approach.
Several compounds have been tested for stent coating, primarily
with the aim of the inhibition of SMC proliferation. Recently,
new stents have emerged which are loaded with anti-inflammatory,
anti-migratory, anti-proliferative or pro-healing drugs.
In this review article the results of clinical studies investigating
drug-eluting stents are discussed from pharmacological and
clinical points of view, reviewing the current literature
and the future prospective.
[Back to top]
Carvedilol: Just Another Beta-Blocker or a Powerful
Cardioprotector?
R.S. Carreira, P. Monteiro, L.M. Gonçalves and
L.A. Providência
Beta-blockers have been used to treat ischemic heart
disease, due to negative chronotropic and inotropic properties,
thus inducing a decrease in myocardial consumption of oxygen
and nutrients, allowing a better balance between nutritional
needs and the supply provided by the coronary blood flow.
Recent developments in cell biology allowed us to understand
that not all beta-blockers are equal, as their intracellular
mechanisms of action can be very different.
This paper will focus on carvedilol, a non-selective beta-blocker
with alfa-blocker properties, currently used to treat hypertension,
heart failure and coronary artery disease. Effects of carvedilol
on cardiac mitochondria, their relation to its antioxidant
properties, and how these can improve cardiomyocyte resistance
to aggression and cardiac function will be discussed.
We will begin by depicting the effect of carvedilol on mitochondrial
parameters, namely oxidative phosphorylation, calcium homeostasis
and energy production. Then we will focus on the mitochondrial
permeability transition (MPT) and how the antioxidant properties
of carvedilol can be used to minimize oxidative stress, a
powerful inducer of MPT. Carvedilol will also be highlighted
as an enzyme modulator, focusing on its importance to prevent
doxorubicin (DOX) cardiotoxicity. The mitochondrial-related
mechanism of cardioprotection involving carvedilol will also
be addressed, as we will discuss some clinical pieces of evidence
showing the importance of mechanisms previously depicted.
In conclusion, based upon its molecular mechanisms of action,
carvedilol seems to be a unique beta-blocker. These unique
characteristics can help us understand the positive impact
of carvedilol on the prognosis of patients with heart disease.
[Back to top]
Novel Insights Into Lp(a) Physiology and Pathogenicity:
More Questions Than Answers?
Marlys L. Koschinsky
Lipoprotein(a) (Lp(a)) is of interest to both basic researchers
who endeavour to understand the mechanism of action of this
unique lipoprotein, as well as to clinicians who are interested
in the contribution of Lp(a) to cardiovascular risk profiles.
The Lp(a) particle contains a moiety that is indistinguishable
from circulating LDL, covalently linked to the unique glycoprotein
component apolipoprotein(a) (apo(a)). Since the 1970s, epidemiological
data have been accumulated that, on balance, indicate that
elevated plasma Lp(a) concentrations are an independent risk
factor for vascular diseases. Apo(a) is highly homologous
to the fibrinolytic proenzyme plasminogen, containing many
tandemly-repeated kringle motifs similar to several of those
found in the plasminogen molecule; the size of the kringle
domain in apo(a) gives rise to Lp(a) isoform size heterogeneity
which is a hallmark of this lipoprotein. The similarity between
Lp(a) and plasminogen led to speculation of a bridging role
for Lp(a) in atherothrombotic disease based on the duality
of the structure of this lipoprotein. In this scenario, LDL
would contribute to the proatherosclerotic properties of the
particle, while apo(a) would interfere with the normal fibrinolytic
functions of plasminogen, thereby inhibiting the breakdown
of thrombi formed in the vasculature. Many in vitro
and in vivo studies have suggested a prothrombotic
role for Lp(a) which is attributable to the apo(a) component
of the particle. However, there are a number of unique properties
that apo(a) confers to Lp(a) which are independent of its
similarity to plasminogen. These include the ability of apo(a)/Lp(a)
to affect platelet function, to contribute to endothelial
dysfunction, and to inhibit the clearance of chylomicron remnant
particles in a transgenic mouse model. Very recent data have
revealed a potential role for Lp(a) in the preferential binding
of oxidized phospholipid adducts through one of the kringle
motifs in apo(a). Many questions remain to be answered regarding
the role of Lp(a) in atherothrombotic disease. This article
will review the relevant literature concerning the contribution
of Lp(a) to risk for both atherosclerotic and purely thrombotic
disorders, as well as the proposed mechanisms of Lp(a) pathogenicity
related to the structure of this lipoprotein. Emerging areas
of interest in the field including the role of apo(a) isoform
size as a risk factor for CHD – independent of Lp(a)
levels – will also be discussed, as will speculation
as to the possible physiological role of Lp(a). Future directions
in the field as well as recommendations for the use of Lp(a)
in clinical contexts will also be addressed.
[Back to top]
Anti-Inflammatory Effects of Different Drugs/Agents
with Antioxidant Property on Endothelial Expression of Adhesion
Molecules
Yung-Hsiang Chen, Shing-Jong Lin, Yuh-Lien Chen, Po-Len
Liu and Jaw-Wen Chen
Atherosclerosis is a chronic inflammatory process. The adhesion
of leukocytes to the vascular endothelium, mediated by endothelial
cell adhesion molecules including vascular adhesion molecule-1
(VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and
E-selectin, is the pivotal early event in atherogenesis. Inflammatory
cytokines could activate redox-sensitive transcription factors
and induce endothelial expression of adhesion molecules, which
could be inhibited to various degrees by different antioxidants
suggesting the potential role of endogenous reactive oxygen
species (ROS) in atherogenesis.
Many clinical drugs that against cardiovascular diseases have
exhibited antioxidant effects; these drugs simultaneously
inhibit endothelial adhesion molecule expression, such as
aspirin, probucol, HMG-CoA reductase inhibitors, angiotensin
receptor blockers, angiotensin converting enzyme inhibitors,
peroxisome proliferator-activated receptor α
and γ
ligands, calcium channel blockers, β-adrenergic
blockers, etc. In addition, we have previously demonstrated
that Ginkgo biloba extract, a Chinese herb with antioxidant
activity, could significantly suppress inflammatory cytokine-stimulated
endothelial adhesiveness to human monocytic cells by attenuating
intracellular ROS formation, redox-senstive transcription
factor activation, and VCAM-1 as well as ICAM-1 expression
in human aortic endothelial cells. The similar anti-atherosclerosis
effects have been also shown in other Chinese herbs or dietary
supplements with antioxidant activity such as magnolol and
salvianolic acid B either in vitro or in vivo.
Thus, oxidative stress is critical to endothelial adhesiveness
in atherogenesis. The inhibition of endothelial adhesion molecule
expression by drugs/agents with antioxidant activity may serve
as a potential therapeutic strategy for clinical atherosclerosis.
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