|
Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 5, Number 4, October 2007
Contents
Strategies to Reduce Vascular Risk Associated
with Obesity Pp. 249-258
Peter F. Bodary, Heidi B. Iglay and Daniel T. Eitzman
[Abstract]
Saving the Ischemic Penumbra: Potential Role for Statins
and Phosphodiesterase Inhibitors Pp. 259-265
Fabrizio Sallustio, Marina Diomedi, Diego Centonze and
Paolo Stanzione
[Abstract]
Microcirculatory Endothelial Dysfunction During Endotoxemia
– Insights into Pathophysiology, Pathologic Mechanisms
and Clinical Relevance Pp. 266-275
Marcus Czabanka, Christoph Peter, Eike Martin and Andreas
Walther
[Abstract]
Structural and Functional Alteration of Blood Vessels
Caused by Cigarette Smoking: An Overview of Molecular Mechanisms
Pp. 276-292
Mohammad M. Rahman and Ismail Laher
[Abstract]
Monitoring of the Antiplatelet Drugs Effect in Patients
with Coronary Artery Disease: What is the Real Clinical Impact?
Pp. 293-301
Luc Christiaens and Laurent Macchi
[Abstract]
Vascular Pleiosynergy – Does It Really Work?
Pp. 302-304
Albert Császár
[Abstract]
Near-Infrared Spectroscopy (NIRS): A Non-Invasive
In Vivo Methodology for Analysis of Brain Vascular
and Metabolic Activities in Real Time in Rodents
Pp. 305-321
Francesco Crespi
[Abstract]
Closure of Patent Foramen Ovale: When and How?
Pp. 322-327
Veronica Lisignoli, Alberto M. Lanzone, Dennis Zavalloni,
Paolo Pagnotta and Patrizia Presbitero
[Abstract]
Abstracts
[Back to top]
Strategies to Reduce Vascular Risk Associated
with Obesity
Peter F. Bodary, Heidi B. Iglay and Daniel T. Eitzman
The obesity pandemic will likely have a significant impact
on the global incidence of cardiovascular disease. Although
the mechanisms linking obesity and cardiovascular disease
are unclear, recent studies have implicated the adipocyte
as a potentially important mediator of vascular complications.
The adipocyte is no longer considered a passive storage depot
for triglycerides and fatty acids, but rather an active metabolic
organ capable of producing several factors, commonly referred
to as adipokines, that may have effects on many physiological
and pathophysiological processes. With increasing fat mass,
several adipose-related factors are upregulated that may affect
local and distant inflammatory processes, including atherothrombosis.
Other factors, such as adiponectin, are downregulated with
increasing fat mass. Although most adipokines are thought
to promote vascular disease, several studies over the past
few years indicate adiponectin is actually protective against
both diabetes and vascular disease. There are now available
pharmacologic agents capable of altering the adipocyte transcription
profile. This review will focus on the potential impact of
adipocyte-derived factors towards vascular disease and emerging
therapeutic strategies that may alter these effects.
[Back to top]
Saving the Ischemic Penumbra: Potential Role for Statins
and Phosphodiesterase Inhibitors
Fabrizio Sallustio, Marina Diomedi, Diego Centonze and
Paolo Stanzione
Ischemic stroke is the third cause of death and the most common
cause of neurological disability. A main target of treatment
is the still salvageable tissue surrounding the core of infarction
and called “ischemic penumbra”. Up to now the
only drug approved for the treatment of acute ischemic stroke
is recombinant tissue plasminogen activator to achieve early
arterial recanalization and hypoxic tissue reperfusion and
improve neural function. However, thrombolytic therapy has
to be administered soon after the event since its efficacy
is time dependent. This intervention also carries an increased
risk of hemorrhagic transformation.
In the rescue of poorly perfused cerebral regions an important
role is played by collateral blood supply through the circle
of Willis and through small pial vessels surrounding the lesion.
The extent of collateralization is variable and at least in
part regulated by the modulation of arteriolar nitric oxide
(NO)-dependent endothelial function. Drugs that can improve
endothelial function and cerebrovascular reactivity could
have a role in collateral formation and infarct volume limitation.
Statins affect endothelial NO production demonstrating their
potential to influence endothelial NO synthase (eNOS) and
in treating stroke.
Phosphodiesterase (PDE) inhibitors improve functional recovery
after stroke in rats enhancing neuro and synapto genesis and
increasing guanosine 3,5-cyclic monophosphate (cGMP).
The aim of this review is to highlight the potential of these
two classes of drugs in the treatment of acute ischemic stroke
by analysing their pharmacological effects and involvement
in the NO and cGMP pathways.
[Back to top]
Microcirculatory Endothelial Dysfunction During Endotoxemia
– Insights into Pathophysiology, Pathologic Mechanisms
and Clinical Relevance
Marcus Czabanka, Christoph Peter, Eike Martin and Andreas
Walther
Alterations in microcirculatory permeability are a characteristic
of early tissue injury. Moreover, tissue edema is an early
indicator of tissue dysfunction, prior to organ failure, because
tissue edema is associated with impaired gas exchange, arterial
hypoxemia, and may also impair tissue oxygen distribution.
As a result of increased microvascular permeability, plasma
fluid is lost into the interstitial space, leading to hypovolemia.
Currently, no effective pharmacological therapy is available
to reduce increased permeability.
High mortality rate in sepsis is still mainly associated with
endothelial damage. In this regard platelets, besides leukocytes,
play a major role for the development of microvascular hyperpermeability.
This review considers endothelial cell dysfunction during
endotoxemia including current insights into sepsis pathophysiology.
New aspects of this complex pathogenesis are illustrated and
their relevance for clinical sepsis therapy is emphasized.
[Back to top]
Structural and Functional Alteration of Blood Vessels
Caused by Cigarette Smoking: An Overview of Molecular Mechanisms
Mohammad M. Rahman and Ismail Laher
Smoking is a significant independent risk factor for cardiovascular
disease and is a leading cause of structural and functional
alterations of the cardiovascular system. Most clinical and
experimental investigations of the pathophysiology of cigarette
smoking have studied the effects of smoke as a whole, while
a few studies focused on specific components of cigarette
smoke, e.g. nicotine and carbon monoxide, which are only 2
of the more than 4,000 different chemicals present in cigarette
smoke. The findings point to some discrepancies when the effects
of whole smoke are compared to nicotine alone, while there
is almost uniform agreement that both active and passive smoking
have detrimental effects on the cardiovascular system, although
a milder effect was suggested for the latter.
This review focuses on findings from clinical and experimental
studies on the vascular effects of active and passive cigarette
smoking and nicotine exposure. The findings are discussed
in terms of tissue (conduit vs. resistance arteries and veins),
species, age, gender and dosage. Although the exact pathophysiology
of cigarette smoking has not been unveiled, cigarette smoking
causes injury to the vascular endothelium, produces superoxide
anions, reduces production and bioavailability of nitric oxide
(NO), increases production and release of endothelin, causes
endothelial dysfunction, thrombosis, atherosclerosis, infarction,
coronary artery disease (CAD), stroke and death.
[Back to top]
Monitoring of the Antiplatelet Drugs Effect in Patients
with Coronary Artery Disease: What is the Real Clinical Impact?
Luc Christiaens and Laurent Macchi
Antiplatelet therapy is used to reduce the risk of ischemic
events in patients with cardiovascular disease. The balance
of benefits and risks of antiplatelet drugs in coronary artery
disease has been evaluated in large-scale randomised trials,
however the absolute benefit for an individual patient and
a specific platelet-active drug need further evaluation. Several
well-conducted studies have demonstrated a substantial inter-individual
variability in the platelet responsiveness to drugs. The historical
“gold standard” test of platelet function (optical
aggregation) has well established limitations for measuring
the effect of antiplatelet drugs. Other new tests developed
(i.e. PFA-100®,
VerifyNow®)
may overcome some of these limitations but they do not correlate
well with each other. Despite these unresolved methodological
questions, several recent clinical studies, but not all, suggest
a significant correlation between antiplatelet resistance
status and serious vascular events. In these conditions, laboratory
monitoring for antiplatelet therapies raises several questions:
(i) the necessity for a consensus on the definition of resistance
and on the best test for evaluation of the condition, (ii)
the demonstration that biological resistance has clinical
significance, and (iii) the clinical impact of adapting the
antiplatelet therapy. Therefore, it is not currently appropriate
to test patients or to change therapy on the basis of such
tests, other than in prospective and adequately powered clinical
trials.
[Back to top]
Vascular Pleiosynergy – Does It Really Work?
Albert Császár
Cardiovascular risk increases exponentially by multiple risk
factors. Similarly, by simultaneously treating these risk
factors the therapeutic benefit can be multiplied. It is also
relevant that some drugs exert extra benefit by acting beyond
their main effect. A wide range of pleiotropic effects have
been reported among lipid lowering statins and third-generation
calcium channel blockers. These include an increase of endothelial
nitric oxide (NO) production, inhibition of free radical formation
and reduction of migration and proliferation of smooth muscle
cells independently from the main therapeutic effect of these
drugs. Favorable “therapeutic cross effects” due
to pleiotropic mechanisms can be defined as pleiosynergy.
[Back to top]
Near-Infrared Spectroscopy (NIRS): A Non-Invasive
In Vivo Methodology for Analysis of Brain Vascular
and Metabolic Activities in Real Time in Rodents
Francesco Crespi
Near infrared spectroscopy (NIRS) was first used as a tool
for the in vivo monitoring of tissue oxygenation
in the late seventies. Today, NIRS instruments are more and
more used in clinical environments since they are now easy
to use, sensitive, robust, provide rapid analysis and could
be complementary to other non invasive methodologies such
as functional magnetic resonance imaging (fMRI) and positron
emission tomography (PET).
The feasibility of non-invasive analysis of brain activities
is studied in the attempt to overcome the major limitation
of invasive in vivo methodologies. In the present
work, optic fibre probes were used as optical head of a novel,
highly sensitive near infrared continuous wave spectroscopy
(CW-NIR) instrument adapted for in vivo NIRS measurements
in the brain of rodents. This prototype was designed for non-invasive
analysis of the 2 main forms of haemoglobin: oxy-haemoglobin
(HbO2) and deoxy-haemoglobin
(Hb), chromophores present in biological tissues as these
are markers of the degree of tissue oxygenation, thus providing
an index of blood level and therefore of tissue metabolism.
It was first tested in peripheral tissue (human gastrocnemius
muscle) and then reset to perform measurement on rat brain.
In animal studies, the optical head was firmly placed using
stereotaxic apparatus upon the sagittal line of anaesthetised
adult rat’s head, without any surgery.
‘Physiologic’ (i.e. with exogenous oxygen (O2)
or carbon dioxide (CO2) supplied
orally) or pharmacologic (i.e. with drugs of abuse such as
cocaine) experiments have been performed to support the effectiveness
of the methodology in preclinical studies. In addition, the
possibility that changes in brain metabolism as measured by
NIRS might be a useful index of brain penetration of new chemical
entities has been investigated using different compounds from
different chemical classes that were selected on the basis
of their known brain penetration and overall pharmacokinetic
profile.
Finally, the feasibility of coupling NIRS with another although
invasive in vivo method such as electrophysiology
for concomitant analysis of cerebral cell firing in discrete
brain areas was tested in the attempt to study in real time
the putative correlation between blood levels, brain metabolism
and neuronal activities in rat CNS, i.e. apply NIRS to pharmacodynamic
investigations. The data gathered in rat treated with exogenous
O2, indicate an original
relationship between NIRS analysis of brain metabolism and
electrical changes in this major nucleus of CNS involved in
neurophysiologic and pathologic activities.
[Back to top]
Closure of Patent Foramen Ovale: When and How?
Veronica Lisignoli, Alberto M. Lanzone, Dennis Zavalloni,
Paolo Pagnotta and Patrizia Presbitero
Percutaneous closure of a patent foramen ovale (PFO)
was performed in 98 consecutive patients (mean age 52.5 ±
13 years, 61 women). Indications included recurrent
transient ischaemic attack (47%), cryptogenic stroke (34%),
peripheral embolism (11%), disabling migraine with aura (4%),
professional scuba diving (1 pt) and severe platypnea-orthodeoxia
syndrome (1 pt). Each PFO was characterized by transesophageal
echocardiography (TEE) according to anatomy, degree of shunt
(1-mild, 2-moderate, 3-severe), right atrial anatomical features
relevant for PFO closure (such as presence of an Eustachian
valve, Chiari network, lipomatosis or absence of septum secundum)
with a new classification scheme.
According to this classification successful device delivery
was obtained in 100% of pts. Major complications included
heparin-induced thrombocytopenia in 1 pt and device dislodgment
in 1 pt; minor complications were mostly related to the catheter
introduction site (2 pts) and mild immediate shunt (2 pts).
In conclusion, percutaneous PFO closure based on strict anatomic
criteria is a safe procedure with minimal periprocedural complications.
|
