Cardiovascular
& Hematological Disorders - Drug Targets
ISSN: 1871-529X
Current Drug Targets - Cardiovascular
& Hematological Disorders
Volume 7, Number 3, September 2007
Contents
Heparin Induced Thrombocytopenia: Pathogenetic, Clinical,
Diagnostic and Therapeutic Aspects Pp. 153-162
R. Castelli, E. Cassinerio, M.D. Cappellini, F. Porro,
G. Graziadei and F. Fabris
[Abstract]
Melatonin in Cardiac Ischemia/Reperfusion-Induced
Mitochondrial Adaptive Changes Pp. 163-169
C.G. Giacomo and M. Antonio
[Abstract]
Peculiarities of the Anticoagulant Properties for
the Newly Synthesized Preparations of Coumarin-Related Compounds
Pp. 170-173
A.V. Ghazaryan, A.S. Khatchadourian, M.K. Karagyozyan,
A.R. Kachatryan, E.S. Sekoyan, H.K. Bdoyan, H.V. Melkumyan
and K.G. Karageuzyan
[Abstract]
Refined Echocardiographic Assessment and Contemporary
Medical Treatment of Obstructive Hypertrophic Cardiomyopathy
Pp. 174-187
C. de Gregorio
[Abstract]
Na+/Ca2+
Exchange Inhibitors: A New Class of Calcium Regulators
Pp. 188-198
T. Iwamoto , Y. Watanabe, S. Kita and M.P. Blaustein
[Abstract]
Endocarditis Due to Salmonella Enterica Subsp. Arizonae
in a Patient with Sickle Cell Disease: A Case Report and Review
of the Literature Pp. 199-204
I. Starakis, D. Siagris, C. Karatza, H. Solomou and H.
Bassaris
[Abstract]
Endoplasmic Reticulum Stress as a Novel Therapeutic
Target in Heart Diseases Pp. 205-218
A. Toth, P. Nickson, A. Mandl, M.L. Bannister, K. Toth
and P. Erhardt
[Abstract]
B-lymphocytes as Targets for Therapy in Chronic Cold
Agglutinin Disease Pp. 219-227
S. Berentsen, E. Ulvestad and G.E. Tjønnfjord
[Abstract]
Abstracts
[Back to top]
Heparin Induced Thrombocytopenia: Pathogenetic, Clinical,
Diagnostic and Therapeutic Aspects
R. Castelli, E. Cassinerio, M.D. Cappellini, F. Porro,
G. Graziadei and F. Fabris
Heparin induced thrombocytopenia (HIT) in addition to bleeding
complications are the most serious and dangerous side effects
of heparin treatment. HIT remains the most common antibody
mediated, drug–induced thrombocytopenic disorder and
a leading cause of morbidity and mortality. Two types of HIT
are described: Type I is a transitory, slight and asymptomatic
reduction of platelet count occurring during 1-2 days of therapy.
HIT type II, which has an immunologic origin, is characterized
by a thrombocytopenia that generally onset after the fifth
day of therapy. Despite thrombocytopenia, haemorrhagic complications
are very rare and HIT type II is characterized by thromboembolic
complications consisting in venous and arterial thrombosis.
The aim of this paper is to review new aspects of epidemiology,
pathophysiology, clinical features, diagnosis and therapy
of HIT type II. There is increasing evidence that platelet
factor 4 (PF4) displaced from endothelial cells, heparan sulphate
or directly from the platelets, binds to heparin molecule
to form an immunogenic complex. The anti-heparin/PF4 IgG immune
complexes activates platelets through binding with the Fc
RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia
and thrombosis. Cytokines are generated during this process
and inflammation could play an additional role in the pathogenesis
of thromboembolic manifestations. The onset of HIT type II
is independent from dosage, schedule, and route of administration
of heparin. A platelet count must be carried out prior to
heparin therapy. Starting from the fourth day, platelet count
must be carried out daily or every two days for at least 20
days of any heparin therapy regardless of the route of the
drug administration. Patients undergoing orthopaedic or cardiac
surgery are at higher risk for HIT type II. The diagnosis
of HIT type II should be formulated on basis of clinical criteria
and confirmed by in vitro demonstration of heparin-dependent
antibodies detected by functional and antigen methods. However,
the introduction of sensitive ELISA tests to measure anti
heparin/PF4 antibodies has showed the immuno-conversion in
an higher number of patients treated with heparin such as
the incidence of anti-heparin/PF4 exceeds the incidence of
the disease. If HIT type II is likely, heparin must be immediately
discontinued, even in absence of certain diagnosis of HIT
type II, and an alternative anticoagulant therapy must be
started followed by oral dicumaroids, preferably after resolution
of thrombocytopenia. Further studies are required in order
to elucidate the pathogenetic mechanism of thrombosis and
its relation with inflammation; on the other hand large clinical
trials are needed to confirm the best therapeutic strategies
for HIT Type II.
[Back to top]
Melatonin in Cardiac Ischemia/Reperfusion-Induced
Mitochondrial Adaptive Changes
C.G. Giacomo and M. Antonio
Due to its small size and amphiphilic nature, indoleamine
melatonin is able to reach all cell compartments quickly.
The highest Melatonin concentrations are to be found in the
mitochondria, and cytochrome c (cyt c) represents a Melatonin
target, since Melatonin is able to oxidise organic molecules
in the presence of physiological amounts of hydrogen peroxide
(H2O2).
The mitochondrial cyt c-mediated oxidation of melatonin depends
on oxoferrylheme in two oneelectron steps. The protective
effects of Melatonin against cardiac ischemia/reperfusion
(I/R)-induced mitochondrial oxidative damage are well documented
as an antioxidant agent which prevents and/or modulates the
production of reactive oxygen species (ROS) responsible for
the reperfusion injury. On the basis of our previous studies
on ischemia/reperfusion (I/R) in human cardiomyocytes it has
become clear that severe hypoxic and ischemic stimuli evoke
a mitochondrial response in terms of the functional adaptation
of cyt c oxidase (COX) to oxygen altered availability. Most,
if not all, data are compatible with a mechanism of adaptation,
in which nitric oxide (NO) generation is now considered as
the major player. The NO-induced COX inhibition represents
a key point in ischemia-induced, adaptive changes, since a
balanced oxidative metabolism between lower O2
concentrations and COX catalytic capacity down-regulation
is thus obtained. This mechanism is a limiting factor in the
cardiac ischemia-induced ROS mitochondrial generation. In
the light of this concept and if we consider melatonin to
be strongly active in cyt c up-regulation, it is obvious that
the use of this molecule in the course of cardiac ischemia
could be deleterious. On the contrary, the prompt restoration
of the coronary blood flow is inexorably associated with the
so called “reperfusion syndrome” and/or with a
condition of myocardial stunning. These phenomena are strictly
linked to the aforementioned ischemia-induced cyt c adaptive
changes, for the reason that a primary imbalance is induced
between the persistent down-regulated enzymatic oxidative
capacity and mitochondrial oxygen gradients are rapidly restored.
This leads to a massive ROS neo-generation, which evokes well-known
cellular disorders. In this scenario the melatonin
treatment could play a pivotal role in terms of a cyt c up-regulating
agent, crucial for counteracting most, if not all the biochemical
and molecular phenomena, on which the clinical symptoms proper
of myocardial reperfusion syndrome are based.
[Back to top]
Peculiarities of the Anticoagulant Properties for
the Newly Synthesized Preparations of Coumarin-Related Compounds
A.V. Ghazaryan, A.S. Khatchadourian, M.K. Karagyozyan,
A.R. Kachatryan, E.S. Sekoyan, H.K. Bdoyan, H.V. Melkumyan
and K.G. Karageuzyan
a) Objectives: Investigations of the four synthetic coumarin-related
compounds: N’ – allylthiouridine-3- carbamoil
coumarin (GSH-16), N’- morpholylthiouridine-3-carbamoil
coumarin (GSH 17), N’–O-fluor-benzyl-N’-3-
carbamoil piperaside coumarin (GSH-10) and 6-nitroallylamide-3-carboxy
coumarin (GSH-84), were done for study of their role in the
processes of hemocoagulation.
b) Design and Methods: Investigations were carried out on
120 white rats (180-200g), which were injected intravenously
by 0.5 ml and 1.0 ml of 1 % solution of GSH-17 and decapitated
after 10 and 30 min after the injection by use of light chloroform
narcosis. Separation of the liver was done by simultaneous
washing with cold physiological solution.
c) Results: It was shown that the hemostabilization action
of GSH 17 is highly dose- and time – dependent, with
by the pronounced decrease of rat liver thromboplastic activity
after 10 and especially 30 min following intravenous injection.
d) Conclusion: One of the possible mechanisms for haemostatic
effect of the studied preparations, particularly GSH-17, probably
can be accepted their effect on metabolism of arachidonic
acid by lipoxygenase and cycloxygenase mechanisms [9, 10].The
results of this investigations have not only the academic
interest, but they have also a significant importance for
definite branches of practical medicine as a very effective
blood stabilizing factors.
[Back to top]
Refined Echocardiographic Assessment and Contemporary
Medical Treatment of Obstructive Hypertrophic Cardiomyopathy
C. de Gregorio
Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease,
relatively common among genetic disorders. The prevalence
is about 1:500 in the general population. Obstructive type
occurs in about 25% of the cases.
The clinical course is heterogeneous due to the large variety
of genetic-based phenotypes with different prognostic impact.
Primary HCM is one of the most important causes of sudden
death in young people and may be a medical problem in athletes
with physiologic left ventricular hypertrophy. In the last
decade, however, several studies reported normal longevity.
Echocardiography has emerged as the most important noninvasive
method to make diagnosis and provide classifications of the
disease.
In this commentary, some out of the most recent and sophisticated
applications of this method in HCM are reported. The most
common pathophysiologic aspects and a proposal of classification
of the obstruction-causing mechanisms, like systolic anterior
motion of the mitral valve, papillary hypertrophy and dislocation,
chordal slack, mid-cavity obliteration, are described.
Some recent studies on coronary blood flow velocity and coronary
reserve, performed by sophisticated Doppler echocardiography,
have demonstrated important pathophysiological insights on
microcirculatory impairment in patients with HCM.
At present, advanced echocardiography surely improves the
clinical management of these patients, and contributes to
optimize the therapeutic strategies. However, the most appropriate
framework of tests to be performed in the majority of them
still remains a challenging clinical matter.
[Back to top]
Na+/Ca2+
Exchange Inhibitors: A New Class of Calcium Regulators
T. Iwamoto , Y. Watanabe, S. Kita and M.P. Blaustein
The Na+/Ca2+exchanger
(NCX) is a bidirectional transporter that normally extrudes
Ca2+ from the cell (forward
mode), but also brings Ca2+
into the cell (reverse mode) under special conditions such
as intracellular Na+ (Na+
i) accumulation or membrane
depolarization. There are three mammalian NCX isoforms: NCX1
is widely expressed in the heart, kidney, brain, blood vessels,
and so on; whereas the expression of NCX2 and NCX3 is limited
mainly to the brain and skeletal muscle. The pharmacology
of NCX inhibitors has been studied extensively since the development
of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in
1996. Currently, experiments are actively progressing with
more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly,
the inhibitory potency of benzyloxyphenyl NCX inhibitors is
directly coupled to the rate of Na+
i-dependent inactivation.
Therefore, the benzyloxyphenyl inhibitors are apparently dormant
during the forward mode under normal conditions (low Na+
i), but become effective
during the reverse mode under pathological conditions (high
Na+ i).
This should be an ideal profile for calcium regulators against
Na+ i-related
diseases, such as ischemia/reperfusion injuries, salt-dependent
hypertension, and digitalis arrhythmia. Existing ion channel
blockers, such as amiodarone, dronedarone, bepridil, aprindine,
and cibenzoline, have been found to have an NCX inhibitory
action. It is possible that this property is partly responsible
for their antiarrhythmic and cardioprotective effects. This
article presents the characteristics of selective and non-selective
NCX inhibitors and their therapeutic potential as a new calcium
regulator.
[Back to top]
Endocarditis Due to Salmonella Enterica Subsp. Arizonae
in a Patient with Sickle Cell Disease: A Case Report and Review
of the Literature
I. Starakis, D. Siagris, C. Karatza, H. Solomou and H.
Bassaris
Human cases due to Salmonella enterica subsp. arizonae are
especially rare, but it may affect immunocompromised patients
and infants. We present a case of endocarditis in a patient
with sickle cell disease and a review of earlier cases caused
by this rare human pathogen. The patient was successfully
treated with ceftriaxone and ciprofloxacin. There are only
few cases of salmonella endocarditis reported in the last
six decades and it is the first case of Salmonella enterica
subsp. arizonae endocarditis in the literature to the best
of our knowledge.
[Back to top]
Endoplasmic Reticulum Stress as a Novel Therapeutic
Target in Heart Diseases
A. Toth, P. Nickson, A. Mandl, M.L. Bannister, K. Toth
and P. Erhardt
The endoplasmic reticulum (ER) is a multifunctional organelle
responsible for the synthesis and folding of proteins as well
as calcium storage and signaling. Perturbations of ER function
cause ER stress leading to the unfolded protein response (UPR),
which includes inhibition of protein synthesis, protein refolding
and clearance of misfolded proteins. The UPR aims at restoring
cellular homeostasis, however, prolonged ER stress can trigger
apoptosis. ER stress-induced apoptosis has been implicated
in the pathogenesis of various diseases such as brain ischemia/reperfusion,
neurodegeneration, diabetes and, most recently, myocardial
infarction and heart failure. Initial events leading to UPR
and apoptosis in the heart include protein oxidation and disturbed
calcium handling upon ischemia/reperfusion, and forced protein
synthesis during cardiac hypertrophy. While XBP-1 and ATF6-mediated
induction of ER chaperones seems to protect the heart from
ischemia/reperfusion injury, the PERK/ATF4/CHOP branch of
the UPR might transmit proapoptotic signals. The precise mechanism
of ER stress-induced cardiomyocyte apoptosis remains elusive,
however, recent data suggest that the mitochondrial apoptotic
machinery is recruited through the upregulation of Puma, a
proapoptotic member of the Bcl-2 family. Importantly, suppression
of Puma activity prevented both ER stress and ischemia/reperfusion-induced
cardiomyocyte loss, highlighting the ER stress pathways as
potential therapeutic targets in cardiovascular diseases.
[Back to top]
B-lymphocytes as Targets for Therapy in Chronic Cold
Agglutinin Disease
S. Berentsen, E. Ulvestad and G.E. Tjønnfjord
Primary chronic cold agglutinin disease (CAD) is an autoimmune
hemolytic anemia induced by cold reactive autoantibodies (cold
agglutinins) against erythrocyte surface antigens. Corticosteroids
or alkylating agents have been used in the treatment of CAD,
but the results have been disappointing.
The cold agglutinins in CAD patients are monoclonal immunoglobulins,
usually of the IgM type encoded by the VH4-34
gene segment. Flowcytometric assessment of lymphocytes from
bone marrow aspirates and immunohistochemical assessment of
biopsy samples have revealed a monoclonal CD20+κ+
B lymphocyte population in 90% of the patients.
These pathogenetic features have provided a basis for novel
therapies in primary CAD. Infusions of rituximab, a chimeric
human-murine anti-CD20 antibody known to be effective in B-cell
lymphoma, produced partial response rates of approximately
50% and occasional complete responses. Median response duration,
however, was only 11 months. Complement C3 and C4 depletion
in many CAD patients, as well as Fcγ-RIIIa
receptor polymorphism, have been proposed as explanations
for the inconstant efficacy of rituximab therapy. In order
to increase response rates and response duration, we are undertaking
a phase 2 study of rituximab and fludarabine combination therapy.
The preliminary results are encouraging, but further studies
are required in order to allow firm conclusions.
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