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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 10, 2006
Contents
Molecular and Clinical Aspects of Hereditary Hemorragic
Telangiectasia: A Rare Disease
Executive Editor: Emilo Jirillo
Editorial Pp. 1169
Introduction: Hereditary Hemorrhagic Telangiectasia as a Rare
Disease Pp. 1171-1172
E. Daina, F. D'Ovidio and C. Sabbà
[Abstract]
Hereditary Haemorrhagic Telangiectasia (HHT): Genetic
and Molecular Aspects Pp. 1173-1193
G.M. Lenato and G. Guanti
[Abstract]
Involvement of the Transforming Growth Factor
β in the Pathogenesis
of Hereditary Hemorrhagic Teleangiectasia Pp. 1195-1200
E. Jirillo, L. Amati, P. Suppressa, D. Cirimele, E. Guastamacchia,
V. Covelli, E. Tafaro and C. Sabbà
[Abstract]
Ablation of T-Helper 1 Cell Derived Cytokines and
of Monocyte-Derived Tumor Necrosis Factor-α
in Hereditary Hemorrhagic Teleangiectasia: Immunological Consequences
and Clinical Considerations Pp. 1201-1208
L. Amati, M.E. Passeri, F. Resta, V. Triggiani, E. Jirillo
and C. Sabbà
[Abstract]
Patients with Hereditary Hemorrhagic Telangectasia
(HHT) Exhibit a Deficit of Polymorphonuclear Cell and Monocyte
Oxidative Burst and Phagocytosis: A Possible Correlation with
Altered Adaptive Immune Responsiveness in HHT Pp.
1209-1215
A. Cirulli, M.P. Loria, P. Dambra, F. Di Serio, M.T. Ventura,
L. Amati, E. Jirillo and C. Sabbà
[Abstract]
HHT: A Rare Disease with A Broad Spectrum
of Clinical Aspects Pp. 1217-1220
C. Sabbà, M. Gallitelli, G. Pasculli, P. Suppressa,
F. Resta, Guastamacchia and E. Tafaro
[Abstract]
HHT in Childhood: Screening for Special
Patients Pp. 1221-1225
P. Giordano, A. Nigro, G.C.Del Vecchio, C. Sabbà
and D. De Mattia
[Abstract]
Hereditary Haemorrhagic Teleangiectasia:
Diagnostic Imaging of Visceral Involvement Pp.
1227-1235
M. Memeo, A. Scardapane, A.A. Stabile Ianora, C. Sabbà
and G. Angelelli
[Abstract]
Treatment of Recurrent Epistaxis in HHT
Pp. 1237-1242
U.W. Geisthoff, M.L. Fiorella and R. Fiorella
[Abstract]
Endovascular Treatment of Pulmonary and Cerebral Arteriovenous
Malformations in Patients Affected by Hereditary Haemorrhagic
Teleangiectasia Pp. 1243-1248
E. De Cillis, N. Burdi, A.S. Bortone, D. D’Agostino,
T. Fiore, G.C.Ettorre and M. Resta
[Abstract]
The Need for an Interdisciplinary Network of Investigations
on HHT Pp. 1249-1251
G. Pasculli, G. Sallustio and C. Sabbà
[Abstract]
Drugs in Interventional Cardiology
Executive Editor: Peter W. Radke
Editorial Pp. 1253
Biology and Pharmacology of the Platelet P2Y12
Receptor Pp.1255-1259
R.F. Storey
[Abstract]
Clopidogrel Resistance: Implications for Coronary
Stenting Pp. 1261-1269
P.A. Gurbel, W.C. Lau, K.P. Bliden and U. Tantry
[Abstract]
Thienopyridines and Statins: Assessing a Potential
Drug-Drug Interaction Pp. 1271-1280
H. Neubauer and A. Mügge
[Abstract]
Thienopyridines in Percutaneous Coronary Interventions:
Standard Procedures and High Risk Subsets Pp. 1281-1286
P.W. Radke, R. Hoffmann, A. Zernecke, A. Kaiser,
H. Schunkert and C. Weber
[Abstract]
The Role of Antiplatelet Agents in the Management
of Patients Receiving Intracardiac Closure Devices Pp.
1287-1291
A. Franke and H.P. Kühl
[Abstract]
Primary and Secondary Stroke Prevention with Antiplatelet
Drugs Pp. 1293-1297
H-C. Diener
[Abstract]
Abstracts
[Back
to top]
Editorial
Hereditary Hemorragic Teleangiectasia or Osler-Weber-Rendu
disease represents a rare genetic disorder which is under
intensive investigation in view of its multidisciplinary aspects.
In the present hot topic issue entitled: “Molecular
and Clinical Aspects of Hereditary Hemorragic Telangiectasia:
A Rare Disease” the full spectrum of this disease has
been emphasized starting from basic concepts to diagnostic
criteria and innovative therapeutic procedures.
In the first paper of this special issue Daina and associates
[1] have pointed out the salient features of Hereditarry Hemorragic
Telangiectasia (HHT), stating that this disease is more frequent
than previously estimated and, therefore, diagnostic and therapeutic
technologies have improved the recognition of the disease.
Lenato and Guanti [2] have provided information about genetic
and molecular aspects of HHT, claiming that the variability
observed among members of the same family has not yet been
explained , despite the sharing of the same disease-causing
mutation.
In three consecutive papers the immulological aspects of HHT
have been investigated. The role of Transforming Growth Factor-beta
in the regulation of the immune response and of cellular proliferation
has been discussed [3]. In addition, novel findings demonstrate
that in HHT patients the T-helper (h)-1 response is ablated,
while the Th2 response seems to dominate the immune scenario
[4]. This defect of the adaptive immunoresponse could down-regulate
the phagocytic activity, as observed in another group of patients
[5].
Sabbà and associates [6] have outlined the broad spectrum
of clinical manifestation observed in all organs in HHT patients.
Giordano and associates [7] have placed emphasis on the pediatric
aspects of HHT with the aim to establish reliable screening
protocols for the prevention and cure of the disease.
Memeo and associates [8] have illustrated some diagnostic
imaging procedures for visceral involvement and, in particular,
ultrasonography seems to be the best screening modality for
hepatic and pulmonary localizations. Geisthoff and associates
[9] have reviewed all the therapeutical treatments for recurrent
hepistaxis in HHT. Endovascular treatment of pulmonary and
cerebral arteriovenous malformations in HHT patients has been
presented by De Cillis and associates [10].
Finally, Pasculli and associates [11] have concluded that
appropriate screening programs are mandatory and multispecialistic
cooperation is needed. Special Centers developed in the world
are currently working to formulate better therapeutical approaches
for HHT based on gene therapy in order to cure this condition.
References
[1] Daina E, D’Ovidio F, Sabbà C. Introduction:
Hereditary Hemorragic Telangiectasia as a rare disease. Curr
Pharm Design 2006; 12(10): 1171-1172.
[2] Lenato GM, Guanti G. Hereditary Haemorrhagic Telangiectasia
(HHT): genetic and molecular aspects. Curr Pharm Design 2006;
12(10): 1173-1193.
[3] Jirillo E, Amati L, Suppressa P, Cirimele D, Guastamacchia
E, Covelli V, Tafaro E, Sabbà C. Involvement of the
transforming growth factor
β in the pathogenesis of hereditary
hemorrhagic teleangiectasia. Curr Pharm Design 2006; 12(10):
1195-1200.
[4] Amati L, Passeri ME, Resta F, Triggiani V, Jirillo E,
Sabbà C. Ablation of T-Helper 1 cell derived cytokines
and of monocyte-derived tumor necrosis factor
β in hereditary hemorrhagic
teleangiectasia: immunological consequences and clinical considerations.
Curr Pharm Design 2006; 12(10): 1201-1208.
[5] Cirulli A, Loria MP, Dambra P, Di Serio F, Ventura MT,
Amati L, Jirillo E, Sabbà C. Patients with hereditary
hemorrhagic telangectasia (HHT) exhibit a deficit of polymorphonuclear
cell and monocyte oxidative burst and phagocytosis: a possible
correlation with altered adaptive immune responsiveness in
HHT. Curr Pharm Design 2006; 12(10): 1209-1215.
[6] Sabbà C, Gallitelli M, Pasculli G, Suppressa P,
Resta F, Guastamacchia E, Tafaro E. HHT: a rare disease with
a broad spectrum of clinical aspects. Curr Pharm Design 2006;
12(10): 1217-1220.
[7] Giordano P, Nigro A, Del Vecchio GC, Sabbà C, De
Mattia D. HHT in childhood: screening for special patients.
Curr Pharm Design 2006; 12(10): 1221-1225.
[8] Memeo M, Scardapane A, Stabile Ianora AA, Sabbà
C, Angelelli G. Hereditary hemorrhagic teleangiectasia: diagnostic
imaging of visceral involvement. Curr Pharm Design 2006; 12(10):
1227-1235.
[9] Geisthoff UW, Fiorella ML, Fiorella R. Treatment of recurrent
epistaxis in HHT. Curr Pharm Design 2006; 12(10): 1237-1242.
[10] De Cillis E, Burdi N, Bortone AS, D’Agostino D,
Fiore T, Ettorre GC, Resta M. Endovascular treatment of pulmonary
and cerebral arteriovenous malformations in patients affected
by hereditary hemorrhagic teleangiectasia. Curr Pharm Design
2006; 12(10): 1243-1248.
[11] Pasculli G, Sallustio G, Sabbà C. The need for
an interdisciplinary network of investigations on HHT. Curr
Pharm Design 2006; 12(10): 1249-1251.
Emilio Jirillo
Immunologia, Policlinico
Piazza G. Cesare 4
70124, Bari
Italy
[Back to top]
Introduction: Hereditary Hemorrhagic Telangiectasia
as a Rare Disease
E. Daina, F. D'Ovidio and C. Sabbà
A disease is considered rare in the United States when it
affects one individual per 1, 250 and one individual per 2,
000 in Europe. Most rare diseases (RD) are of genetic origin;
their rarity involves a difficult and/or late diagnosis. The
greatest barrier to prevention, diagnosis and treatment of
RD is inadequate knowledge. Hereditary haemorrhagic telangiectasia
(HHT) is a “rare” genetic disorder that is becoming
more commonly recognised. Recent evidence indicates that it
is more frequent (1-2/10, 000) than previously estimated.
We suppose that the frequent misdiagnosis and the different
genetic penetrance have led to an underestimation of real
prevalence. In fact, progress in scientific knowledge and
improvement in diagnostic and therapeutic technologies has
unmasked conditions which were not fully known previously,
determining a fictitious decrease in disease frequency.
[Back to top]
Hereditary Haemorrhagic Telangiectasia (HHT): Genetic
and Molecular Aspects
G.M. Lenato and G. Guanti
Hereditary Haemorrhagic Telangiectasia, or Rendu-Osler-Weber
syndrome, is a rare autosomal dominant disorder involving
the vascular system and is characterised by a highly variable
expressivity and age-dependent penetrance. Diagnosis is based
on the presence of at least three of four of the following
symptoms: spontaneous epistaxis, cutaneous telangiectases,
arteriovenous malformations in internal organs and familiarity.
Recurrent complications are severe anaemia, stroke, portal
and pulmonary hypertension. The peculiar characteristic of
this disease is the diffusion of arte-riovenous malformations,
that is, localised abnormal arteriovenous connections affecting
both microvasculature and large vessels. HHT is actually a
heterogenous genetic disorder, divided into two clinically
indistinguishable forms: HHT1 caused by mutations in endoglin
gene mapping on chromosome 9q, and HHT2 caused by mutations
in ALK1 located on chromosome 12q. Haploinsufficiency
is the underlying mechanism for endoglin and most ALK1
mutations. Such mutations lead to a deficiency in angiogenesis,
i.e. the sprouting of new vessels from pre-existing ones.
To date, little is still known about the mechanism(s) responsible
for lesion formation, development and slow growth. Current
models focus on the role that TGF-β
superfamily members, a vast group of multifunctional cytokines,
play in endothelial responses to angiogenic stimuli. As both
genes seem to act in TGF-β
signal transduction pathways, SMAD proteins are also thought
to be involved. There is no clear explanation accounting for
the strong variability shown even among members of the same
family despite the sharing of the same disease-causing mutation,
and why lesions are spatially discrete.
[Back to top]
Involvement of the Transforming Growth Factor
β in the
Pathogenesis of Hereditary Hemorrhagic Teleangiectasia
E. Jirillo, L. Amati, P. Suppressa, D. Cirimele, E. Guastamacchia,
V. Covelli, E. Tafaro and C. Sabbà
Hereditary hemorrhagic telangiectasia (HHT) is characterized
by vessel alterations such as dilatation of postcapillary
venules and arterio-venous communications, which account for
the major clinical manifestations of the disease. Two types
of HHT have been characterized HHT-1 and HHT-2, respectively,
depending the former on endoglin mutations and the latter
on activin receptor-like kinase 1 (ALK-1) mutations. Both
endoglin and ALK-1 bind to the transforming growth factor
(TGF) superfamily which, physiologically, regulates the activities
of endothelial cells and also those related to the extracellular
matrix. In this review, the salient features of TGF-β
will be outlined with special reference to its activity on
the immune system and on tumorigenesis. Furthermore, the involvement
of TGF-β
in the pathogenesis of some gastrointestinal diseases will
be discussed and, in particular, in the course of liver disease,
Helicobacter pylori infection and inflammatory bowel
disease. In the light of these data and of animal model of
HHT, the potential risk of developing other diseases in HHT
patients will be discussed.
[Back to top]
Ablation of T-Helper 1 Cell Derived Cytokines and
of Monocyte-Derived Tumor Necrosis Factor-α
in Hereditary Hemorrhagic Teleangiectasia: Immunological Consequences
and Clinical Considerations
L. Amati, M.E. Passeri, F. Resta, V. Triggiani, E. Jirillo
and C. Sabbà
Experimental evidences on the adaptive immune response in
patients with hereditary hemorragic telagiectasia (HHT) are
lacking. Here, we report in 9 patients with HHT a multiple
deficit involving the intracellular expression of T helper
(h)1-derived cytokines [Interferon (IFN)-γ,
Interleukin (IL)-2 and Tumor Necrosis Factor (TNF)-α]
and of monocyte-derived TNF-α.
On the other hand, percentages of Th2-derived cytokines (IL-4,
IL-5 and IL-10) were normal or, in some cases, above normality.
Quite interestingly, monocyte-derived IL-10 was detectable
in 5 out of 9 patients in a percentage of cells comparable
to controls or exceeding normal levels. Taken together, these
data point out, in HHT, an ablation of Th1-responses, while
Th2-type cytokines are preserved, thus exerting either a suppressive
effect on Th1-cells (via IL-4 and IL-10) or an antiinflammatory
response on monocyte-derived TNF-α
(via IL-10). Furthermore, monocyte-derived IL-10
may also contribute to the antiinflammatory activity seen
in HHT. According to current literature even if patients with
HHT do not exhibit certain diseases, such as autoimmune diseases,
cancer and abnormal responses to pathogens, the observed immune
deficits need to be diagnosed and therapeutically corrected.
[Back to top]
Patients with Hereditary Hemorrhagic Telangectasia
(HHT) Exhibit a Deficit of Polymorphonuclear Cell and Monocyte
Oxidative Burst and Phagocytosis: A Possible Correlation with
Altered Adaptive Immune Responsiveness in HHT
A. Cirulli, M.P. Loria, P. Dambra, F. Di Serio, M.T. Ventura,
L. Amati, E. Jirillo and C. Sabbà
Hereditary Hemorrhagic Telangiectasia (HHT)
is a rare genetic disease characterized by mutations occurring
in the endoglin and ALK-1, two receptors of transforming growth
factor-β1.
From a pathogenic point of view, a possible involvement of
the immune system in HHT has been suggested since a mononuclear
cell infiltrate was found around the area of telangiectases.
Up until now, no information has been available about the
role played by leukocytes in HHT and the mechanisms elicited
by secretion of their mediators. However, the fact that a
deficit of adaptive immunity in HHT has been reported in a
companion paper in this issue will represent a great contribution
to the understanding of HHT pathogenesis.
The purpose of this study was to evaluate whether patients
with HHT manifest also alterations in the innate immune response.
Therefore, the phenotype of T, B and natural killer lymphocytes,
serum immunoglobulin levels, phagocytosis and oxidative burst
activity exerted by polymorphonuclear cells (PMN) and monocytes
(MO) were analyzed in 22 patients. Twenty individuals demonstrated
single or multiple deficits of PMN and MO functions, while
the immunopheno-type of lymphocytes and serum concentrations
of immunoglobulins were normal.
To the best of our knowledge, this is the first demonstration
of a reduction in PMN and MO functions in HHT, thus suggesting
a higher susceptibility to infectious complications in these
patients. The relationship between innate immune deficits
and T helper 1 and monocyte-derived cytokine dysfunction in
HHT, as previously reported, is discussed.
[Back to top]
HHT: A Rare Disease with A Broad Spectrum of Clinical
Aspects
C. Sabbà, M. Gallitelli, G. Pasculli, P. Suppressa,
F. Resta, Guastamacchia and E. Tafaro
HHT is an autosomal dominant disease characterised by
diffuse muco-cutaneous and visceral telangiectases in potentially
all organs. Mutations in two different genes identify HHT
type 1 and HHT type 2: endoglin located on chromosome 9q33-q34
and ALK-1 or ACVRL1 on chromosome 12q13, respectively. The
existence of a third locus has also been hypothesised. HHT-1
is considered a more severe form of the disease with an earlier
onset of epistaxis and telangiectases and a higher prevalence
of pulmonary arteriovenous malformations than that found in
HHT-2 subjects. Usually, a typical HHT patient has epistaxis,
muco-cutaneous telangiectases and GI bleeding in later life,
even though this clinical scenario represents only one of
the possible HHT patterns. In fact, vascular malformations
often remain silent until the onset of a severe complication,
which frequently is the first clinical manifestation of HHT.
The lung and brain are of particular concern because each
may contain clinically silent lesions that can result in sudden
morbidity and mortality. At present, awaiting the availability
of genetic testing, only an expert in the clinical patterns
and diagnostic imaging of HHT can permit a definite diagnosis
in individuals at high risk for the disease.
[Back to top]
HHT in Childhood: Screening for Special Patients
P. Giordano, A. Nigro, G.C.Del Vecchio, C. Sabbà
and D. De Mattia
Hereditary hemorrhagic telangiectasia
(HHT) or the Rendu-Osler-Weber disease is a systemic fibrovascular
autosomal dominant dysplasia, recognised when three of the
following four clinical manifestations are present, according
to the proposal of Shovlin.: recurrent nosebleeds, lelangiectasias
of the skin, visceral lesions, and positive family history.
HHT is often difficult to diagnose on the basis of history
and physical examination alone, especially in infants and
children. The signs and symptoms of HHT are nonspecific and
are extremely variable within families. Given the frequent
occurrence of clinically silent lesions in lung and brain
arteriovenous malformations which can result in morbidity
or death, much consideration should be given to screening
patients with HHT for asymptomatic fistulae and to their treating
once they are discovered. Presymptomatic interventions in
such cases may substantially affect the outcome. It may be
possible to state that lesions of HHT arise early in life,
but do not reach sufficient size to cause symptoms until the
second decade. Furthermore, as clinical manifestations often
occur later in life, the development and the implementation
of a molecular diagnosis will allow the identification of
subjects with no evident signs of the disease but carrying
the familial mutation. This is fundamental in order to establish
reliable screening protocols for the prevention and cure of
the disease and, to determine the presence of family members
with no disease-associated mutation, who do not require further
clinical screening.
[Back to top]
Hereditary Haemorrhagic Teleangiectasia: Diagnostic
Imaging of Visceral Involvement
M. Memeo, A. Scardapane, A.A. Stabile Ianora, C. Sabbà
and G. Angelelli
Hereditary Haemorrhagic Telangiectasia
(HHT), also known as Rendu-Osler-Weber disease, is an autosomal-dominant
vascular disease characterised by mucocutaneous or visceral
angiodysplastic lesions (telangiectases and arteriovenous
malformations), which may be widely distributed throughout
the cardiovascular system. Its diagnosis is based on clinical
criteria. Liver, lungs and brain, in order of prevalence,
are the most frequently involved visceral districts of the
body other than skin and nasal mucosa. Liver involvement is
frequent and characterised by the presence of intrahepatic
shunts, disseminated intraparenchymal telangiectases and other
vascular lesions. Although it is usually asymptomatic, congestive
cardiac failure, portal hypertension, portosystemic encephalopathy,
cholangitis or atypical cirrhosis are possible complications.
Pulmonary arteriovenous malformations involve more than one
third of HHT patients and can consist of diffuse telangiectases
or high-flow low-pressure shunts between pulmonary arteries
and veins. Pulmonary involvement can cause serious complications:
hypoxaemia, pulmonary or pleural hemorrhage, paradoxical embolism
into cerebral circulation. Various types of cerebrovascular
malformations can affect HHT patients and the most common
are arteriovenous malformations, consisting of one or more
feeding arteries connected to one or more draining veins.
Diagnostic imaging has a fundamental role in detecting the
alterations involving these various districts in the body.
The possibility to perform fast and complete studies and to
provide high quality multiplanar and angiographic reconstructions,
gives multi-detector row helical computed tomography and magnetic
resonance the ability to detect and characterise the complex
anatomo-pathological alterations typical of HHT. Ultrasonography
seems to be the best screening modality for hepatic and pulmonary
involvement.
[Back to top]
Treatment of Recurrent Epistaxis in HHT
U.W. Geisthoff, M.L. Fiorella and R. Fiorella
No optimal treatment modality is currently
available for the treatment of recurrent epistaxis in HHT.
In this review, different therapeutic concepts are discussed
together with their pathophysiologic background. Patients
often profess a preventive effect for nasal ointments and
use packings which can be self-administed in the case of bleeding.
An effective first-line treatment for physicians is the endonasal
laser coagulation or argon plasma coagulation. A second line
surgical procedure is septodermoplasty according to Saunders
which can provide long-lasting relief if performed correctly.
There have been reports on antifibrinolytic agents and hormones,
but their efficacy has yet to be determined.
[Back to top]
Endovascular Treatment of Pulmonary and Cerebral Arteriovenous
Malformations in Patients Affected by Hereditary Haemorrhagic
Teleangiectasia
E. De Cillis, N. Burdi, A.S. Bortone, D. D’Agostino,
T. Fiore, G.C.Ettorre and M. Resta
Hereditary Haemorrhagic Teleangiectasia
(HHT) is a vascular disorder of angiogenesis transmitted in
an autosomal dominant pattern, characterised by heterogeneity
in clinical manifestations. One of the most important organ
involved is lung, including pulmonary arteriovenous malformations
(PAVM). PAVM occur in 20 to 30% of the HHT population and
recently are considered a marker of disease. PAVM are direct
artery-to-vein connections with low pressure and without an
interveining capillary bed. PAVM are classified as simple
(supplied by one feeding artery) or complex (receiving blood
supply from two or more feeding artery). According to the
international reports, treatment it’s recommendable
for all PAVM with feeding vessels 3mm or larger, in order
to reduce the risk of cerebral ischaemia and neurologic manifestations
frequently attributed to paradoxical embolisation. Transcatheter
embolotherapy of PAVM is a form of treatment based on occlusion
of the feeding artery to a PAVM by using platinum coils or
detachable balloons. The technique of coil embolisation involves
the exact localisation of PAVM by pulmonary angiography followed
by superselective percutaneous caheterisation of feeding artery
obtained by using a dedicated 7F guiding catheter, which coaxially
allocates a 5F hydrophilic catheter advanced in order to perform
both superselective angiography of feeding artery and embolisation
itself. Inside the 5F catheter the platinum coils are advanced
using a .035” guide-wire and released until an optimal
occlusion of feeding artery is achieved. At the end of the
procedure angiographic control is performed in order to verify
the occlusion of feeding artery. The use of platinum coils
is preferable over detachable balloons when feeding artery
are greater than 7mm in diameter and have irregular anatomical
configuration. On the other hand, the principal advantage
of using detachable balloons is that the balloon itself can
be deflated and repositioned if necessary. Transcatheter embolotherapy
is technically safe and clinically effective and may represent
the primary choice of treatment in HHT patients. On the other
hand the most common complications of this treatment (pleurisy
and air embolism) can be prevented by using some tips during
the embolisation procedure like “anchor technique,”
“scaffold technique” and “balloon assisted
technique.”
Cerebral arteriovenous malformations (CAVM) are present in
10-20% of patients with HHT and multiple in 50% of cases.
Cortical surface is the most frequent localisation. Angiography
is needed to diagnose all CAVM and to clarify the angioarchitecture
of the lesion. In HHT CAVM are usually either micro-AVM, with
a nidus not bigger than 1 cm, or small AVM, with a nidus between
1 and 3 cm. Quite frequently there are lesions characterised
by arteriovenous fistulas.
In the three patterns of CAVM usually found in HHT, small
AVM are the most risky for bleeding although the risk is lower
than that associated with sporadic ones. It is estimated from
0.38 to 0.69% per year in spite of the general incidence of
bleeding in sporadic CAVM that ranges from 2 to 4% per year.
In HHT patients, at present, the precise indications and timing
of treatment are not established. Trend is to treat small
AVM and AVF and to follow-up micro-AVM with MRI and angiography.
As for sporadic CAVM, treatment of small AVM is usually referred
to stereotactic radiosurgery. Endovascular embolisation is
proposable if the lesion is easily reachable by microcatheterism
and the position of the microcatheter is safe. Glue is used
for embolisation and the technique is briefly discussed.
[Back to top]
The Need for an Interdisciplinary Network of Investigations
on HHT
G. Pasculli, G. Sallustio and C. Sabbà
In the last years, the understanding of HHT has greatly progressed.
The two genes for most on cromosomes 9 and 12 have been discovered
and the existence of a third involved gene has been predicted.
Recent progress in the field of genetics has allowed the identification
of many gene mutation thus facilitating the characterisation
of the at risk members of the same family. Complications from
bleeding or shunting (pulmonary AVMs) may be sudden and life-threatening
(hemothorax, haemoptysis, stroke and brain abscess). Catastrophic
events are preventable by early diagnosis and treatment. Appropriate
screening programmes are mandatory and multi-specialistic
cooperation is needed. Special centers have been developed
in the world, where physicians, who are specialised and trained
in all aspects of HHT, are working to develop better therapeutic
approaches for the disease and to locate new genes in view
of the future potential of gene therapy for this condition.
[Back to top]
Editorial
Atherothrombotic diseases and especially coronary and cerebrovascular
diseases are the most important causes of death in industrialized
countries. The use of platelet aggregation inhibitors in this
context improves morbidity and mortality. The effect of acetylsalicylic
acid (ASA) as an inhibitor of the cylooxygenase is well established
as shown in numerous major trial.
In recent years, the dual role of P2Y1 and P2Y12 receptors
in platelet aggregation by ADP has been firmly established.
Thienopyridines act as inhibitors of the P2Y12 receptor with
beneficial effects in atherothrombotic diseases, either as
a stand alone therapy or in combination with aspirin.
In this edition of “Drugs in interventional cardiology”,
the variety of indications for thienopyridines will be discussed.
In the first article, Robert F. Storey will provide an overview
on the biology and pharmacology of the platelet P2Y12
receptor [1]. Thereafter, potential problems associated with
thieonopyridine treatment will be mentioned. Gurbel and co-workers
discuss the phenomenon and clinical implications of clopidogrel
resistance [2] before potential drug-drug interaction between
thienopyridines and statins will be summarized by Neubauer
and Mügge [3].
Our group from Lübeck and Aachen will discuss indications
for thienopyridines in percutaneous coronary interventions
[4] before Franke and Kühl will evaluate the role of
antiplatelet agents in the management of patients receiving
intracardiac closure devices [5]. Finally, Prof. Diener will
provide an up-to-date review on primary and secondary stroke
prevention using antiplatelet drugs [6].
I would like to thank all authors for their contribution.
References
[1] Storey RF. Biology and pharmacology of the platelet P2Y12
receptor. Curr Pharm Design 2006; 12(10): 1255-1259.
[2] Gurbel PA, Lau WC, Bliden KP, Tantry U. Clopidogrel Resistance:
Implications for Coronary Stenting. Curr Pharm Design 2006;
12(10): 1261-1269.
[3] Neubauer H, Mügge A.Thienopyridines and Statins:
Assessing a Potential Drug-Drug Interaction. Curr Pharm Design
2006; 12(10): 1271-1280.
[4] Radke PW, Hoffmann R, Zernecke A, Kaiser A, Schunkert
H, Weber C. Thienopyridines in percutaneous coronary interventions:
Standard procedures and high risk subsets. Curr Pharm Design
2006; 12(10): 1281-1286.
[5] Franke A, Kühl HP. The role of antiplatelet agents
in the management of patients receiving intracardiac closure
devices. Curr Pharm Design 2006; 12(10): 1287-1291.
[6] Diener HC. Primary and Secondary Stroke Prevention with
Antiplatelet Drugs. Curr Pharm Design 2006; 12(10): 1293-1297.
Peter W. Radke
Medical Clinic II
University of Schleswig-Holstein
Campus Lübeck
Ratzeburger Allee 160
D-23538 Lübeck
Germany
E-mail: radke@innere2.uni-luebeck.de
[Back to top]
Biology and Pharmacology of the Platelet P2Y12
Receptor
R.F. Storey
Platelets possess two receptors for ADP, P2Y1
and P2Y12. ADP is released from platelet dense
granules upon platelet activation by numerous agonists and
thereby amplifies platelet responses regardless of the initial
stimulus. The P2Y1 receptor is one of many platelet
receptors coupled to Gq and initiates ADP-induced activation.
The P2Y12 receptor on the other hand is linked
to Gi and plays a special role in the amplification of platelet
activation initiated by numerous other pathways. Platelet
activation leads to a range of responses that play a critical
role in arterial thrombosis and the inflammatory responses
associated with this, including platelet aggregation, dense
and α
granule secretion and procoagulant activity. P2Y12
receptor activation yields powerful amplification of these
processes such that P2Y12 receptor antagonists
may have dramatic inhibitory effects on platelet function
regardless of the activating stimuli. This phenomenon, coupled
with the restricted distribution of the P2Y12 receptor
in humans, makes the receptor an ideal target for pharmaceutical
therapy. This has already been established by the therapeutic
success of clopidogrel, which acts, via an active
metabolite, on this receptor. However, current therapeutic
regimens of clopidogrel yield variable and incomplete P2Y12
receptor blockade and more effective strategies to block P2Y12
receptor activation offer the potential of greater clinical
efficacy.
[Back to top]
Clopidogrel Resistance: Implications
for Coronary Stenting
P.A. Gurbel, W.C. Lau, K.P. Bliden and U. Tantry
Clopidogrel, in combination wih aspirin, is currently the
drug of choice to prevent thrombosis after coronary stent
implantation. Currently, clopidogrel is administered to the
vast majority of patients without any assessment of platelet
inhibition. Response variability and resistance, however,
definitely occur to clopidogrel treatment. Preliminary data
support the hypothesis that patients with reactive or clopidogrel
nonresponsive platelets are at risk for thrombotic events.
However, the magnitude of the clinical effect remains unknown
and relationship between nonresponsiveness and risk of clinical
events is under-investigated. Several important questions
that must be answered are: A) What is the relation of clopidogrel
resistance and high platelet reactivity to the occurrence
of stent thrombosis, recurrent myocardial infarction, stroke
and death?; B) Is there a threshold of platelet reactivity
that correlates with the onset of thrombotic risk?; and C)
What is the cost of administering clopidogrel to non-responsive
patients? Finally, our understanding of the clinical relevance
of drug resistance and high platelet reactivity should be
facilitated by the use of validated point-of-service devices.
The mechanisms of the response variability to clopidogrel
remain incompletely defined. The contribution of intra- and
extracellular pathways are under investigation.
[Back to top]
Thienopyridines and Statins: Assessing a Potential
Drug-Drug Interaction
H. Neubauer and A. Mügge
Clopidogrel and statins are frequently administered in
patients with ischemic heart disease or other atherothrombotic
manifestations and are effective in the prevention of cardiovascular
disease.
The thienopyridine clopidogrel is a pro-drug metabolised in
the liver via the cytochrome P450 (CYP) 3A4 system
to the active compound which inhibits the P2Y12
ADP platelet receptor. The assumption exists that the effect
of clopidogrel in inhibiting platelet aggregation is attenuated
by co-administration of lipophilic statins such as atorvastatin
or simvastatin which are metabolised by the CYP3A4 system
to inactive substrates. Assessing a possible drug-drug interaction
ex-vivo, inconclusive studies have been published: In an aggregometer
study, a strong and dose-dependent interference between atorvastatin
and the inhibitory effect of clopidogrel on platelet function
was observed. Another study, measuring the effect of clopidogrel
by flow cytometry, found a significant attenuation of the
clopidogrel effect by lipophilic statins, pre-dominantly in
the loading phase. In contrast a recent study, which used
600mg clopidogrel for loading, found no significant interference
between various statins and clopidogrel on ADP-induced platelet
aggregation and in addition another study revealed no attenuation
of the clopidogrel effect despite statin co-medication after
5 weeks.
Additionally, retrospective analysis of clinical studies (CREDO-study)
or registries (MITRA PLUS) revealed no significant influence
of different statins on the clinical outcome in patients treated
with clopidogrel. However, these clinical studies showed a
trend towards a diminishing effect of clopidogrel on those
treated with cytochrome CYP3A4 metabolised statins.
Even more important seems to be the considerable variability
in the response of the antiplatelet effect of clopidogrel.
A certain percentage of patients apparently do not respond
adequately to clopidogrel treatment. This effect of clopidogrel
resistance seems to be more important as the potential interference
between CYP3A4 metabolized statins and clopidogrel. Finally,
up until now sufficient evidence has not been gained to prefer
hydrophil statins on patients receiving clopidogrel co-medication
or when to discontinue the use of statins in clopidogrel treatment.
Prospective studies are necessary in order to evaluate the
magnitude of clopidogrel resistance and the impact of clopidogrel
co-medication as well as to redefine antithrombotic therapy
for this subgroup.
[Back to top]
Thienopyridines in Percutaneous Coronary Interventions:
Standard Procedures and High Risk Subsets
P.W. Radke, R. Hoffmann, A. Zernecke, A.
Kaiser, H. Schunkert and C. Weber
Due to the significant clinical and economic consequences
of subacute stent thrombosis and the use of more complex devices
(brachytherapy, drug eluting stents) in a variety of clinical
situations (i.e. acute coronary syndromes), initiation and
duration of a combined antiplatelet therapy using aspirin
and a thienopyridine drug has become an issue of ongoing discussion
in interventional cardiology. This review will provide a short
introduction into the pathophysiology of stent thrombosis
before standard procedures and critical issues on the use
of thienopyridines in the setting of coronary interventions
are discussed. Furthermore, clinically relevant issues that
are not clearly covered by recommendations or guidelines like
thienopyridines after coronary interventions in patients on
chronic oral anticoagulation are also addressed.
[Back to top]
The Role of Antiplatelet Agents in the Management
of Patients Receiving Intracardiac Closure Devices
A. Franke and H.P. Kühl
Transcatheter closure of septal defects has become a
widely used alternative to surgery or life-long anticoagulant
therapy especially in patients with atrial septal defects
(ASD) and patent foramen ovale (PFO). Post-procedural complications
include thrombus formation on the occluder in about 0-10%
of all cases. Therefore antithrombotic prophylaxis after device
implantation is believed to be necessary, but still is variable
and remains controversial. To date no randomized studies have
been published to assess the optimal anticoagulation strategy.
Thus, therapy is based on empirical data, local experience
and case reports from the literature. The present review tries
to give an overview on most of these mainly retrospective
single center studies and summarizes their results.
Factors influencing the rate of thrombus formation may be
device type, existence of thrombophilic disorders and prophylactic
medication. Thrombus formation has been described for each
of the existing occluder types without a significant difference
between the devices. For antithrombotic prophylaxis, most
centers at present use either acetyl salicylic acid alone
(ASA; 81 to 325 mg) for 6 months or a combination of ASA and
clopidogrel (75 mg) for 6 to 8 weeks followed by ASA for additional
4 to 8 months. Inherited thrombophilic disorders should be
excluded before device implantation in order to adapt antithrombotic
prophylaxis. Follow-up examinations after device implantation
should be performed using TEE within the first 4 weeks after
implantation. Thus, thrombi may be recognized early enough
to extend the antithrombotic regimen in order to avoid surgical
device explantation.
[Back to top]
Primary and Secondary Stroke Prevention with
Antiplatelet Drugs
H-C. Diener
Aspirin is not effective in the primary prevention of stroke.
Patients with TIA or ischemic stroke carry a risk of recurrent
stroke between 5 and 20% per year. In patients with TIA or
ischemic stroke of noncardiac origin antiplatelet drugs are
able to decrease the risk of stroke by 11-15% and the risk
of stroke, MI and vascular death by 15-22%. Aspirin is the
most widely used drug. It is affordable and effective. Low
doses of 50-325 mg aspirin are as effective as high doses
and cause less gastrointestinal side effects. Severe bleeding
complications are dose-dependent. The combination of aspirin
with slow release dipyridamole is superior to aspirin alone
for stroke prevention. Clopidgrel is superior to aspirin in
patients at high risk of recurrence. The combination of aspirin
plus clopidogrel is not more effective than clopidogrel alone
but carries a higher bleeding risk. None of the antiplatelet
agents is able to reduce mortality.
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