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Current Vascular Pharmacology
ISSN: 1570-1611
Current Vascular Pharmacology
Volume 6, Number 4, October 2008
Contents
Editorial:
Pleiotropic Effects of Statins: Implications for a
Wide Range of Diseases Pp. 237-239
Kosmas I. Paraskevas, Vassilios Stathopoulos
and Dimitri P. Mikhailidis
Pharmacotherapy Before and After Endovascular
Repair of Abdominal Aortic Aneurysms Pp. 240-249
Athanasios Saratzis, Nikolaos Saratzis, Nikolaos
Melas and Dimitrios Kiskinis
[Abstract]
Screening Aortic Drug Treatments Through
Arterial Compliance Measurements Pp. 250-257
Mark E. Rentschler and B. Timothy
Baxter
[Abstract]
The Role of C-Reactive Protein in Atherosclerotic
Cardiovascular Disease: An Overview Pp.
258-270
Eleni S. Nakou, Evangelos N. Liberopoulos,
Haralampos J. Milionis and Moses S. Elisaf
[Abstract]
Beyond Cholesterol Lowering: Pleiotropic
Effects of Bile Acid Binding Resins Against Cardiovascular
Disease Risk Factors in Patients with Metabolic Syndrome
Pp. 271-281
Minako Yamaoka-Tojo, Taiki Tojo and
Tohru Izumi
[Abstract]
The Role of Trimetazidine After Acute
Myocardial Infarction Pp. 282-291
Maciej Banach, Jacek Rysz, Aleksander Goch,
Dimitri P. Mikhailidi and Giuseppe M.C. Rosano
[Abstract]
The Cardiac Microvasculature in Hypertension,
Cardiac Hypertrophy and Diastolic Heart Failure Pp.
292-300
Michel R. Hoenig, Cesario Bianchi, Anthony
Rosenzweig and Frank W. Sellke
[Abstract]
The Crosstalk Between Insulin and Renin-Angiotensin-Aldosterone
Signaling Systems and its Effect on Glucose Metabolism and
Diabetes Prevention Pp. 301-312
Giovanna Muscogiuri, Alberto O. Chavez,
Amalia Gastaldelli, Luca Perego, Devjit Tripathy, Mario J.
Saad, Licio Velloso and Franco Folli
[Abstract]
Resistance to Aspirin and Thienopyridines
in Diabetes Mellitus and Metabolic Syndrome Pp.
313-328
Giovanni Anfossi, Isabella Russo and
Mariella Trovati
[Abstract]
Occurrence and Clinical Impact of Microembolic
Signals (MES) in Patients with Chronic Cardiac Diseases and
Atheroaortic Plaques - A Systematic Review Pp.
329-334
Ralf Dittrich and E. Bernd Ringelstein
[Abstract]
Vasorelaxation Caused by Cannabinoids:
Mechanisms in Different Vascular Beds Pp.
335-346
Visitación López-Miranda,
Esperanza Herradón and Mª Isabel Martín
[Abstract]
Thrombosis in Paroxysmal Nocturnal Hemoglobinuria
at a Glance: A Clinical Review Pp. 347-353
Panayiotis D. Ziakas, Loukia S. Poulou
and Anastasia Pomoni
[Abstract]
Abstracts
[Back to top]
Editorial: Pleiotropic
Effects of Statins: Implications for a Wide Range of Diseases
Kosmas I. Paraskevas, Vassilios Stathopoulos
and Dimitri P. Mikhailidis
[Back to top]
Pharmacotherapy Before and After Endovascular Repair of Abdominal
Aortic Aneurysms
Athanasios Saratzis, Nikolaos Saratzis, Nikolaos
Melas and Dimitrios Kiskinis
Endovascular (EVAR) abdominal aortic aneurysm (AAA) repair
has been established as a successful procedure in the short
term and may constitute a viable long-term alternative to
open repair (OR). The procedure has been associated with lower
operative and mid-term morbidity and mortality compared to
OR, but long-term results remain largely controversial. EVAR
has also been associated with a significant risk of implant
and procedure-related complications, such as graft thrombosis
and cardiovascular events, necessitating interventional and
pharmaceutical management. Medical management of patients
undergoing EVAR is required for several different reasons.
Patients with an AAA have an increased risk of cardiovascular
death, necessitating treatment to reduce the overall risk
for cardiovascular events. Treatment is inline with the medical
management of coronary artery disease including anti-platelet
therapy and statins. Anti-platelet therapy is also mandatory
to prevent complications such as graft-limb thrombosis and
peripheral arterial disease (PAD), which is common in patients
with an AAA. Especially in patients with PAD, aspirin, clopidogrel
and statins remain the mainstay of medical management. Unfortunately,
there is a lack of prospective randomised trials concerning
the medical management of patients that have undergone abdominal
aortic endo-grafting.
We review the current literature on the medical treatment
of patients undergoing EVAR, focusing on peri-operative man-agement,
anti-platelet agents and statins.
[Back to top]
Screening Aortic Drug Treatments Through Arterial Compliance
Measurements
Mark E. Rentschler and B. Timothy
Baxter
Abdominal aortic aneurysm (AAA) is a common and deadly problem.
The aortic diameter increases in association with a complex
remodeling process that includes changes in the structure
and content of key proteins, elastin and collagen. As these
changes occur, the tissue mechanical properties also change.
The natural history of AAA is progressive enlargement to a
point of mechanical tissue failure typically followed by death.
Currently, the marker used to predict the risk of impending
rupture is the largest transverse diameter. After reaching
a diameter threshold of 5.5 cm the AAA needs to be surgically
repaired. This criterion does not consider any patient-specific
information or heterogeneity of the AAA that may, in some
cases, lead to rupture before the AAA reaches the standard
intervention threshold. Conversely, in many patients, continued
observation beyond this threshold is safe.
While no medical treatment is yet approved, doxycycline (Doxy)
has been shown to greatly reduce AAA growth in animal models
and has been shown to slow growth in 1 small clinical trial.
While larger prospective randomized trials are needed, one
unknown is what effect Doxy has on the structural integrity
of the aortic wall. That is, does slowed AAA growth, by Doxy
treatment, prevent rupture, or does the wall continue to weaken
and the AAA instead ruptures at a smaller diameter?
Using an established animal model of AAA, we begun to determine
the changes in tissue mechanics compliance of the aorta as
the AAA develops. Our current research is focused on verifying
that these changes mimic the observed changes seen in the
human population as reported by other researchers, so that
we can confidently study how potential drug therapies may
affect wall strength and compliance in the human population.
The long-term objectives are to understand better factors
related to progression of AAA and help verify that drug therapy
with Doxy will decrease the chance of rupture by preventing
wall weakening and maintaining function of the aorta.
[Back to top]
The Role of C-Reactive Protein in Atherosclerotic Cardiovascular
Disease: An Overview
Eleni S. Nakou, Evangelos N. Liberopoulos,
Haralampos J. Milionis and Moses S. Elisaf
C-reactive protein (CRP) is an acute-phase protein, which
has been used in clinical practice as a non specific marker
of inflammation. Many studies have shown that CRP is associated
with atherosclerotic cardiovascular disease. It is currently
unknown if CRP plays an active role as an etiologic factor
in cardiovascular disease. The mechanisms by which CRP may
contribute to the pathogenesis of cardiovascular disease are
poorly understood. The effect of CRP on atherogenesis may
include interactions with other factors of immunity and inflammation,
such as the complement system, as well as a direct effect
of CRP on the cells involved in atherosclerotic lesions.
We review the literature concerning the mechanisms by which
CRP may influence the development of cardiovascular disease
and discuss the findings of clinical studies assessing the
association between CRP and cardiovascular disease.
[Back to top]
Beyond Cholesterol Lowering: Pleiotropic
Effects of Bile Acid Binding Resins Against Cardiovascular
Disease Risk Factors in Patients with Metabolic Syndrome
Minako Yamaoka-Tojo, Taiki Tojo and
Tohru Izumi
Prospective epidemiologic studies have shown that dyslipidemia
and hyperglycemia are major risk factors for atherosclerotic
cardiovascular diseases. Undesirable metabolic conditions
are observed to coexist in patients with metabolic syndrome,
which is an important risk factor for cardiovascular disease.
To prevent cardiovascular disease, a pleiotropic agent is
needed to improve the metabolic disorder in patients with
metabolic syndrome. Bile acid binding resins increase the
fecal excretion of bile acids. The decrease in bile acids
returned to the liver leads to an up-regulation of hepatic
low-density lipoprotein (LDL) receptor activity, which decreases
LDL cholesterol (LDL-C) in the circulation and increases high-density
lipoprotein cholesterol. On the other hand, bile acids can
also regulate the transcription of genes involved in LDL-C
synthesis and cholesterol homeostasis via nuclear
hormone receptors. Consequently, these receptors may represent
novel therapeutic targets for dyslipidemia and provide insight
into the role of the bile acid pathway in other metabolic
processes.
This review focuses on the recent findings on bile acid binding
resins and cardiovascular disease risk factors. Moreover,
known and proposed mechanisms of how bile acid binding resins
may improve glucose and energy metabolism are discussed; these
effects may help to explain the mechanisms by which bile acid
binding resins may reduce cardiovascular disease.
[Back to top]
The Role of Trimetazidine After Acute Myocardial Infarction
Maciej Banach, Jacek Rysz, Aleksander Goch,
Dimitri P. Mikhailidi and Giuseppe M.C. Rosano
“Metabolic treatment” involves the use of
drugs to improve cardiomyocyte function. Trimetazidine is
the most investigated drugs in this group. The ESC 2006 guidelines
on the management of patients with stable angina mention the
efficacy of metabolic treatment in improving physical efficiency
and decreasing the recurrence of pain. The available data
suggest that combined therapy of trimetazidine and haemodynamic
drugs is an effective antianginal treatment that reduces the
risk of pain recurrence (in as many as 64% of patients). The
most recent studies also suggest that trimetazidine might
be effective in patients with acute coronary syndromes, ischemic
cardiomyopathy and heart failure. However, while trimetazidine
has shown beneficial effects on surrogate endpoints in several
small trials its effect on cardiovascular events is uncertain.
Further large randomized studies are needed before its effects
on cardiovascular events can be evaluated.
[Back to top]
The Cardiac Microvasculature in Hypertension, Cardiac Hypertrophy
and Diastolic Heart Failure
Michel R. Hoenig, Cesario Bianchi, Anthony
Rosenzweig and Frank W. Sellke
Recent studies revealed an exceedingly high mortality
with diastolic heart failure that was previously regarded
as relatively benign compared to systolic heart failure. Prominent
risk factors for diastolic heart failure are increasing age,
hypertension and diabetes. These risk factors are associated
with coronary microvascular rarefaction and resultant decreased
coronary flow reserve, thereby rendering the myocardium vulnerable
to ischemia. We discuss the importance of angiogenic gene
programming in preserving the coronary microvasculature, preserving
cardiac function and altering disease course. Further, we
discuss the possible utility of therapies that activate hypoxia
inducible factor-1 in preventing rarefaction of the coronary
microvasculature and maintaining cardiac diastolic function.
[Back to top]
The Crosstalk Between Insulin and Renin-Angiotensin-Aldosterone
Signaling Systems and its Effect on Glucose Metabolism and
Diabetes Prevention
Giovanna Muscogiuri, Alberto O. Chavez,
Amalia Gastaldelli, Luca Perego, Devjit Tripathy, Mario J.
Saad, Licio Velloso and Franco Folli
Essential hypertension is an insulin resistant state.
Early insulin signaling steps are impaired in essential hypertension
and a large body of data suggests that there is a crosstalk
at multiple levels between the signal transduction pathways
that mediate insulin and angiotensin II actions. At the extracellular
level the angiotensin converting enzyme (ACE) regulates the
synthesis of angiotensin II and bradykinin that is a powerful
vasodilator. At early intracellular level angiotensin II acts
on JAK-2/IRS1-IRS2/PI3-kinase, JNK and ERK to phosphorylate
serine residues of key elements of insulin signaling pathway
therefore inhibiting signaling by the insulin receptor. On
another level angiotensin II inhibits the insulin signaling
inducing the regulatory protein SOCS 3. Angiotensin II acting
through the AT1 receptor
can inhibit insulininduced nitric oxide (NO) production by
activating ERK ½ and JNK and enhances the activity
of NADPH oxidase that leads to an increased reactive oxygen
species generation. From the clinical standpoint, the inhibition
of the renin angiotensin system improves insulin sensitivity
and decreases the incidence of Type 2 Diabetes Mellitus (T2DM).
This might represent an alternative approach to prevent type
2 diabetes in patients with hypertension and metabolic syndrome,
(i.e. insulin resistant patients). This review will discuss:
a) the molecular mechanisms of the crosstalk between the insulin
and angiotensin II signaling systems b) the results of clinical
studies employing drugs targeting the renin-angiotensin II-aldosterone
systems and their role in glucose metabolism and diabetes
prevention.
[Back to top]
Resistance to Aspirin and Thienopyridines in Diabetes Mellitus
and Metabolic Syndrome
Giovanni Anfossi, Isabella Russo and
Mariella Trovati
Platelets from patients affected by diabetes mellitus
and metabolic syndrome show an impaired sensitivity to physiological
antiaggregating agents and an enhanced activation state, mirrored
by an increased expression of membrane activation markers;
furthermore, they are more prone to form spontaneous microaggregates
with ADP receptor involvement. These abnormalities are responsible
for a pro-thrombotic condition, contributing to a high cardiovascular
risk.
This pattern of platelet abnormalities provides a strong rationale
for aggressive antiplatelet therapy strongly recommended by
guidelines both in diabetes mellitus and in metabolic syndrome,
not only in the setting of acute coronary syndromes, but also
for the long-term prevention of the cardiovascular events.
Antiplatelet therapy in these pathological conditions, however,
is still a matter of intense debate, especially because a
high prevalence of “resistance” to these drugs
(and to aspirin in particular) has been described in these
patients. This may result in non-significant reductions in
cardiovascular events.
Different factors seem to be involved, including: i) genetic
polymorphisms; ii) hyperglycemia and poor metabolic control;
iii) reduced sensitivity to nitric oxide; iv) a pro-inflammatory
and/or pro-thrombotic status, and, v) increased oxidative
stress.
This review will take into consideration: i) the results of
the most relevant studies addressing the effects of the anti-aggregating
treatment in patients affected by diabetes mellitus and/or
metabolic syndrome, and, ii) the biochemical mechanisms accounting
for the impaired sensitivity to aspirin and thienopyridines
in the above mentioned clinical conditions.
[Back to top]
Occurrence and Clinical Impact of Microembolic Signals (MES)
in Patients with Chronic Cardiac Diseases and Atheroaortic
Plaques - A Systematic Review
Ralf Dittrich and E. Bernd Ringelstein
Background: In various cardiac diseases, thrombembolism
constitutes a major risk, and in these patients clinically
silent microembolic signals (MES) are detectable within the
transcranial Doppler frequency spectrum (TCD) of the major
brain arteries. MES are already an accepted surrogate parameter
of the future risk of stroke in patients with carotid artery
stenosis. The aim of this review is to summarize and evaluate
the data about occurence and clinical impact of MES in patients
with chronic cardiac diseases and to clarify whether cardiogenic
MES can serve as a surrogate parameter of the heart’s
future thrombembolic risk as well.
Methods: We performed a systematic MEDLINE search
and reviewed the currently available literature about chronic
cardiac diseases and atheroaortic plaques leading to MES apart
from cardiosurgical procedures.
Conclusion: The cardiac conditions producing MES
are heterogenous and therefore the prevalence of MES is highly
variable. The data in patients with acute or after myocardial
infarction, endocarditis, patent foramen ovale, mitral valve
prolapse, dilatative cardiomyopathy and intracardiac thrombus
is promising but only small patient cohorts have been investigated
by means of TCD in these categories. MES in atrial fibrillation,
or derived from atheroaortic plaques, have been investigated
more intensively, but again larger cohorts need to be explored
to draw firm conclusions. In all cardiac diseases there is
a lack of large prospective studies allowing to reliably correlating
MES with clinical events. Compared to carotid artery disease,
the current knowledge about the impact of cardiogenic MES
on the patient’s risk is sparse. This should encourage
the clinical research in this promising field.
[Back to top]
Vasorelaxation Caused by Cannabinoids: Mechanisms in Different
Vascular Beds
Visitación López-Miranda,
Esperanza Herradón and Mª Isabel Martín
Cannabinoids (natural, endogenous and synthetic compounds)
produce vasorelaxation in resistance and conduit arteries.
Several putative mechanisms have been proposed to explain
this effect of cannabinoids.
The aim of the present review is to discuss the different
mechanisms involved in the vasorelaxant effect of endogenous
and synthetic cannabinoids in resistance and conduit arteries.
Research on the vascular effects of cannabinoids suggests
that the magnitude of the vasorelaxation and the mechanisms
involved are not identical in all vascular beds with one or
two mechanisms predominating. Either extracellular or intracellular
mechanisms are involved. With regard to the former, the stimulation
of cannabinoid CB1, CB2
or nonCB1/nonCB2
cannabinoid receptors and the stimulation of vanilloid receptors,
transient potential vanilloid receptors, on perivascular nerve
endings with the subsequent release of the vasodilator neurotransmitter
calcitonin gene-related peptide have been described. With
regard to the latter, the main mechanisms implicated include
nitric oxide release, metabolism to vasoactive arachidonic
metabolites or prostanoid analogues, or endothelium derived
hyperpolarising factor release.
The knowledge of these mechanisms is crucial to identify new
therapeutic targets and to understand the consequences in
different vascular beds.
[Back to top]
Thrombosis in Paroxysmal Nocturnal Hemoglobinuria at a Glance:
A Clinical Review
Panayiotis D. Ziakas, Loukia S. Poulou
and Anastasia Pomoni
Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare,
acquired stem cell disorder, with its primary clinical manifestations
being hemolytic anemia, marrow failure and thrombophilia.
Chronic hemolysis, failures of the fibrinolytic system, increased
leukocyte–derived tissue factor levels in plasma, procoagulant
microparticles generated through complement-mediated damage
of platelets and venous endothelium are related to the acquired
hypercoagulable state.
Visceral thrombosis (including hepatic veins and mesenteric
veins), cerebrovascular events and pulmonary embolism predict
a poor outcome. Thrombosis is also associated with significant
morbidity during pregnancy. Depending on the sites of thrombosis,
a score-based probability to predict outcome can be assigned.
Abdominal vein thromboses account for the ma-jority of morbidity
and mortality related to thrombosis, and time-dependent trends
suggest that mortality rates tend to decline, with the advent
of evolution of therapeutic and diagnostic strategies. In
contrast, mortality rates from cerebrovascular events display
no significant decline.
Prompt diagnosis requires both clinical suspicion and sophisticated
imaging techniques, along with multidisciplinary therapeutic
intervention.
In the eculizumab era, a significant reduction of thrombotic
events was observed during therapy, and long-term follow up
is needed to establish any benefit in rates and pattern of
this complication. However, up to now, only bone marrow transplantation
permanently abolishes the coagulation defect.
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