|
Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 6, Number 2, April 2008
Contents
Editorial:
Angiogenesis: A Promising Treatment Option for Peripheral
Arterial Disease Pp. 78-80
Kosmas I. Paraskevas and Dimitri P. Mikhailidis
Editorial:
Has the Time Come for a New Definition of Microalbuminuria?
Pp. 81-83
Asterios Karagiannis, Dimitri P. Mikhailidis, Konstantinos
Tziomalos, Anna I. Kakafika and Vasilios G. Athyros
Mitochondrial MMP Activation, Dysfunction and Arrhythmogenesis
in Hyperhomocysteinemia Pp. 84-92
Karni S. Moshal, Naira Metreveli, Iuliana Frank and Suresh
C. Tyagi
[Abstract]
Atherogenesis in Renal Patients: A Model of Vascular
Disease? Pp. 93-107
Georgios Efstratiadis, Konstantinos Tziomalos, Dimitri P.
Mikhailidis, Vasilios G. Athyros and Apostolos Hatzitolios
[Abstract]
Cardiac Protection by Volatile Anaesthetics: A Review
Pp. 108-111
Giovanni Landoni, Oliviero Fochi and Giorgio Torri
[Abstract]
Hormone Replacement Therapy and Stroke Pp.
112-123
Antonia M.R. Billeci, Maurizio Paciaroni, Valeria Caso
and Giancarlo Agnelli
[Abstract]
Statins for the Prevention of First or Recurrent Stroke
Pp. 124-133
Vasilios G. Athyros, Anna I. Kakafika, Konstantinos Tziomalos
Athanassios A. Papageorgiou and Asterios Karagiannis
[Abstract]
Fondaparinux for the Prevention or Treatment of Venous
ThromboEmbolism Related to Lower Limb Trauma: Evidence Today
Pp. 134-142
Nikolaos K. Kanakaris, Vassilios S. Nikolaou, Theodoros
Tosounidis and Peter V. Giannoudis
[Abstract]
Current Status of Carotid Stenting Pp. 143-147
Ji Sun Kim and Debabrata Mukherjee
[Abstract]
Pathogenesis and Treatment of Secondary Hyperparathyroidism
in Dialysis Patients: The Role of Paricalcitol Pp.
148-153
Mario Cozzolino, Andrea Galassi, Maurizio Gallieni and
Diego Brancaccio
[Abstract]
Abstracts
[Back to top]
Editorial:
Angiogenesis: A Promising Treatment Option for Peripheral
Arterial Disease
Kosmas I. Paraskevas and Dimitri P. Mikhailidis
[Back to top]
Editorial:
Has the Time Come for a New Definition of Microalbuminuria?
Asterios Karagiannis, Dimitri P. Mikhailidis, Konstantinos
Tziomalos, Anna I. Kakafika and Vasilios G. Athyros
[Back to top]
Mitochondrial MMP Activation, Dysfunction and Arrhythmogenesis
in Hyperhomocysteinemia
Karni S. Moshal, Naira Metreveli, Iuliana Frank and Suresh
C. Tyagi
Chronic volume/pressure overload-induced heart failure
augments oxidative stress and activates matrix metalloproteinase
which causes endocardial endothelial-myocyte (EM) uncoupling
eventually leading to decline in myocardial systolic and diastolic
function. The elevated levels of homocysteine (Hcy), hyperhomocysteinemia
(HHcy),are associated with decline in cardiac performance.
Hcy impairs the EM functions associated with the induction
of ventricular hypertrophy leading to cardiac stiffness and
diastolic heart failure. Hcy-induced neurological defects
are mediated by the NMDA-R (N-methyl-D-aspartate (NMDA) receptor)
activation. NMDA-R is expressed in the heart. However, the
role of NMDA-R on cardiac function during HHcy is still in
its infancy. The blockade of NMDA-R attenuates NMDA-agonist-induced
increase in the heart rate. Hcy increases intracellular calcium
and activates calpain and calpain-associated mitochondrial
(mt) abnormalities have been identified in HHcy. Mitochondrial
permeabilization and uncoupling in the pathological setting
is fueled by redox stress and calcium mishandling. Recently
the role of cyclophilin D, a component of the mitochondrial
membrane permeability transition pore, has been identified
in cardiac-ischemia. Mechanisms underlying the potentiation
between NMDA-R activation and mitochondrial defects leading
to cardiac dysfunction during HHcy remain to be elucidated.
This review addresses the mitochondrial mechanism by which
Hcy contributes to the decline in mechano-electrical function
and arrhythmogenesis via agonizing NMDA-R. The putative
role of mitochondrial MMP activation, protease stress and
mitochondrial permeability transition in cardiac conduction
during HHcy is discussed. The review suggests that Hcy increases
calcium overload and oxidative stress in the mitochondria
and amplifies the activation of mtMMP, causing the opening
of mitochondrial permeability transition pore leading to mechano-electrical
dysfunction.
[Back to top]
Atherogenesis in Renal Patients: A Model of Vascular
Disease?
Georgios Efstratiadis, Konstantinos Tziomalos, Dimitri P.
Mikhailidis, Vasilios G. Athyros and Apostolos Hatzitolios
Chronic kidney disease (CKD), and particularly kidney failure,
is associated with accelerated atherosclerosis and approximately
a 20-fold increased risk of cardiovascular death. The majority
of these patients die from complications directly attributed
to atherosclerosis and their life expectancy is decreased.
Established risk factors are involved in the pathogenesis
of this phenomenon. Age, gender, smoking, hypertension, dyslipidaemia
and diabetes mellitus are among the established risk factors.
Inflammation, qualitative lipid disorders (e.g. small dense
low density lipoprotein), vascular calcification and oxidative
stress represent emerging risk factors. The precise mechanism
of atherosclerosis in patients with kidney failure is not
yet known.
CKD might represent a clinical model of atherogenesis. Thus,
the evidence obtained from investigating “renal”
atherogenesis could be of interest in improving our understanding
of this disease process in the non-renal population.
We review the relationship between “renal” and
non-renal atherosclerosis focusing on pathogenesis, risk factors
and clinical events and how they interact with treatment options.
Overall, the “later” stages of CKD may eventually
be considered as a coronary heart disease equivalent condition.
[Back to top]
Cardiac Protection by Volatile Anaesthetics: A Review
Giovanni Landoni, Oliviero Fochi and Giorgio Torri
Ischaemic preconditioning, a response to brief sublethal episodes
of ischaemia leading to a pronounced protection against subsequent
lethal ischaemia, is mimicked by some pharmacological agents.
Halogenated anaesthetics alone exhibit cardioprotective properties
at therapeutic doses, independent of their anaesthetic and
haemodynamic effect, leading to the concept of anaesthetic
preconditioning.
Only recently has research turned to clinical application
of preconditioning protocols, and anaesthetic preconditioning
has indeed been demonstrated in randomised clinical trials
conducted in patients undergoing cardiac surgery-mostly coronary
artery bypass graft. Most of these trials demonstrate cardiac
protection by assessing postprocedural release of cardiac
troponin or early postoperative cardiac function. Few studies
focus on clinical outcomes, and none demonstrates an advantage
in terms of mortality or cardiac morbidity.
A recent meta-analysis, pooling data regarding the use of
desflurane and sevoflurane, found significant reductions of
in-hospital mortality, myocardial infarction rate, intensive
care unit and hospital stay, time on mechanical ventilation
and incidence of long term cardiac events.
In conclusion, the use of desflurane and sevoflurane appears
to yield a better outcome, in terms of mortality and cardiac
morbidity, in patients undergoing cardiac surgery. A definitive
demonstration of this concept represents a difficult task
because of the low mortality rate in modern cardiac surgery
and because of the number of interfering factors.
Whether these cardioprotective properties also exist in non-coronary
surgery settings is still controversial owing to the scarce
available data.
[Back to top]
Hormone Replacement Therapy and Stroke
Antonia M.R. Billeci, Maurizio Paciaroni, Valeria Caso
and Giancarlo Agnelli
Stroke is the third most common cause of death in women and
a major cause of disability. Stroke occurs in older age in
women compared with men. High premenopausal estrogen concentrations
in women are thought to be protective against stroke and cardiovascular
disease. Estrogens are essential for normal reproductive function
and they exert complex and diverse non reproductive actions
on multiple tissues such as neuroprotective effects, vasodilatation,
improved vascular reactivity, antithrombotic effects and lipid
lowering effects.
After menopause estrogen concentrations are depleted and in
the past estrogen replacement therapy was considered as a
potential protective agent against both cardiovascular disease
and stroke. Although the use of hormone therapy was originally
associated with a reduction in the risk of heart disease by
about 50% in observational studies, the results regarding
stroke have been less clear.
In order to investigate the effect of hormone therapy on stroke
risk, randomized controlled trials of cardio-and/or cere-brovascular-disease
prevention in women with established heart disease have been
designed. The Heart Estrogen Progestin Replacement Study included
stroke as secondary outcome. This study did not show any differences
in myocardial infarction (MI) or coronary death (HR 0.99;
95%CI 0.80-1.22) and in stroke rate. In another study, the
Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo
was administered to women with previous ischemic stroke or
transient ischaemic attack (TIA) having a mean age 71. No
differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in
mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while
a trend showing an increased rate of fatal strokes (RR 2.9;
95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients
with final National Institutes of Health Stroke Scale (NIHSS)
0-1: 19 % vs. 33%; p = 0.12) was observed. The Women’s
Health Initiative, a primary prevention study, where conjugated
equine estrogen (CEE) plus medroxyprogesterone acetate/placebo
was utilized, was stopped because of an excess in breast cancer
and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently,
a meta-analysis including 39,769 women participating in 28
trials has been published. Twelve studies were of secondary
prevention and the overall stroke rate was 2%. In the hormone
replacement therapy (HRT) arm there was a 29% increased rate
of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore,
a 56% increased rate of death or dependency after stroke and
a tendency of more fatal stroke were observed. Additionally,
a higher stroke risk was reported in the first year of treatment.
Conclusions: There seems to be no indication for hormone
replacement therapy in the prevention of stroke in women.
Further studies are needed to discover why estrogens have
different effects on the heart and brain. Conventional risk-factors
which could increase the risk of estrogen therapy need to
be identified and as well as more restrictive inclusion and
exclusion criteria such as coagulation parameters and intimal
thickness should be adopted before new randomized trials are
started.
[Back to top]
Statins for the Prevention of First or Recurrent Stroke
Vasilios G. Athyros, Anna I. Kakafika, Konstantinos Tziomalos,
Athanassios A. Papageorgiou and Asterios Karagiannis
This review considers the evidence showing that statins can
prevent first or recurrent stroke or improve its outcome in
subjects at moderate or high risk for cardiovascular disease
(CVD). Data are reviewed according to trial design (observational
or prospective) and baseline CVD risk. Two (ASCOT, CARDS)
out of five primary CVD prevention statin trials showed a
considerable reduction in stroke rates. In two (MIRACL and
PROVE IT) out of five acute coronary syndrome trials, the
prevention of first stroke was significant. Most secondary
prevention trials (4S, CARE, LIPID, HPS, GREACE and TNT) showed
a beneficial effect of statins in stroke prevention. Finally,
SPARCL, the only secondary stroke prevention trial in subjects
without overt coronary heart disease (CHD), showed a significant
reduction in total and ischaemic (fatal and nonfatal) stroke
rate, although a small but significant increase in nonfatal
haemorrhagic stroke was noted. There was also a significant
reduction in CHD-related events.
The possible mechanisms responsible for statin-associated
stroke prevention are discussed. The evidence suggests the
need to consider early and long-term statin treatment (with
substantial low-density lipoprotein cholesterol reduction)
in all patients at high risk of any type of major vascular
event, without discriminating CHD from stroke. Thus, statins
may be beneficial to both the heart and the brain.
[Back to top]
Fondaparinux for the Prevention or Treatment of Venous
ThromboEmbolism Related to Lower Limb Trauma: Evidence Today
Nikolaos K. Kanakaris, Vassilios S. Nikolaou, Theodoros
Tosounidis and Peter V. Giannoudis
Patients with lower limb and pelvic trauma, or undergoing
major orthopaedic surgery represent one of the highest risk
groups for the development of venous thromboembolism (VTE).
A significant number of pharmacological and mechanical agents
have been used for the prophylaxis and treatment of VTE. Fondaparinux
is a relative new pharmacological agent that selectively binds
to antithrombin, and represents a new class of synthetic selective
inhibitors of activated factor X.
Eleven percent of the fondaparinux-related English language
literature, between 2001 and 2007, refers to orthopaedic trauma,
and was the sample assessed for this critical analysis review.
The clinical studies evaluating the safety, efficacy, and
financial implications associated with lower limb orthopaedic
trauma show that fondaparinux has comparable results with
the well-established use of enoxaparin.
However, the scientific community has raised several issues
regarding mostly fondaparinux’s safety, timing of its
1st dose, bleeding side effects, duration of administration
and lack of a reliable reversing agent.
Further trials are necessary focusing on the safety and efficacy
of this drug mostly in relation to clinical relevant outcomes
and to different fields of trauma surgery (pelvis, long bone
fractures and polytrauma patients).
[Back to top]
Current Status of Carotid Stenting
Ji Sun Kim and Debabrata Mukherjee
Stroke is the third most common cause of death worldwide following
ischemic heart disease and cancer and the number one condition
associated with permanent disability. In Western countries,
the yearly incidence of stroke is ~ 0.2% of the population
and the number of stroke-related death is expected to double
over the next 30 years. Studies from the Netherlands and Scotland
showed that stroke accounted for 3% to 5% of their total health
care resources. For 2006, the es-timated direct and indirect
cost of stroke in the United States was ~ 60 billion. Significant
stenosis of the internal carotid artery is responsible for
10% to 20% of all strokes or transient ischemic attacks. Large-scale
randomized clinical trials have established the superiority
of carotid endarterectomy (CEA) over medical management in
patients with high-grade stenosis of the internal carotid
artery, particularly among symptomatic patients.
Although percutaneous carotid revascularization has been performed
since the early eighties, the enthusiasm has long been tempered
by the fear of cerebral embolism. Following the introduction
of emboli protection devices (EPD) around the year 2000, the
number of procedures performed worldwide has grown exponentially.
We review the available studies on carotid stenting and discuss
appropriate use of this procedure. Emphasis is also placed
on optimal long-term pharmacotherapy in patients with carotid
stenosis.
[Back to top]
Pathogenesis and Treatment of Secondary Hyperparathyroidism
in Dialysis Patients: The Role of Paricalcitol
Mario Cozzolino, Andrea Galassi, Maurizio Gallieni and
Diego Brancaccio
Hemodialysis (HD) patients are commonly affected by secondary
hyperparathyroidism (SHPT), in which 3 well-known factors
are usually involved: hypocalcemia, hyperphosphatemia and
calcitriol deficiency. Classically, high parathyroid hormone
(PTH) levels cause bone-associated diseases, such as osteitis
fibrosa and renal osteodystrophy, but more recently it has
been demonstrated the link between SHPT and a systemic toxicity,
with a major role in determining cardio-vascular disease,
including arterial calcification, endocrine disturbances,
compromised immune system, neurobehavioral changes, and altered
erythropoiesis.
Treatment with calcitriol (CT), the active form of vitamin
D, reduces parathyroid hormone (PTH) levels, but may result
in elevations in serum calcium (Ca) and phosphorus (P), increasing
the risk of cardio-vascular calcification in the HD population.
Several new vitamin D analogs have been developed and investigated
with the rationale to treat SHPT with a re-duced risk of hypercalcemia
and hyperphosphatemia in HD patients. Paricalcitol (1,25-dihydroxy-19-nor-vitamin
D2, 19-Nor-D2)
is a vitamin D analog that suppresses PTH secretion with minimal
increases on serum calcium and phosphate levels. It was demonstrated
that paricalcitol prevents vascular calcification in experimental
models of renal failure, compared with calcitriol. Furthermore,
19-Nor-D2 is the first analog
approved for use in HD patients and is available for i.v.
and oral administration, commonly 3 times weekly after HD.
The purpose of the present review is to analyze the pathogenesis
and treatment of SHPT in HD patients, and the role of paricalcitol
in the prevention of arterial calcification.
|
