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Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 14, Number 18, 2008
Contents
Modifying Cardiovascular Risk Factors: Novel Cardiovascular
Targets for Treatment by Noninvasive Imaging Techniques
Executive Editors: Aurelio Leone and Luigi Landini
Editorial: Pp. 1743-1744
Fundamentals in Cardiovascular Imaging Technologies
Pp. 1745-1752
L. Landini, M.F. Santarelli, L. Landini Jr. and V. Positano
[Abstract]
Morphology of Atherosclerotic Plaque: Its Feature
by Imaging Study Pp. 1753-1760
G. Passacquale, C. Ferri and G. Desideri
[Abstract]
Endothelial Function Assessment in Complicated
Hypertension Pp. 1761-1770
A. Virdis, L. Ghiadoni, D. Versari, C. Giannarelli, A.
Salvetti and S. Taddei
[Abstract]
Smoking and Cardiovascular System: Cellular Features
of the Damage Pp. 1771-1777
A. Leone, L. Landini Jr, O. Biadi and A. Balbarini
[Abstract]
Coronary Magnetic Resonance Imaging
Pp. 1778-1786
S. Kelle, R.G. Weiss and M. Stuber
[Abstract]
The Application of NMR Spectroscopy for the Study
of Heart Failure Pp. 1787-1797
M. ten Hove and S. Neubauer
[Abstract]
Radionuclide PET and PET/CT in Coronary Artery
Disease Pp. 1798-1814
D. Neglia, O. Rimoldi, P.A. Kaufmann and P.G. Camici
[Abstract]
General Articles
Role of the Autonomic Nervous System and Neuropeptides
in the Development of Obesity in Humans: Targets for Therapy?
Pp. 1815-1820
J.R. Greenfield and L.V. Campbell
[Abstract]
Engineering Silica Particles as Oral Drug Delivery
Vehicles Pp. 1821-1831
S.P. Rigby, M. Fairhead and C.F. van der Walle
[Abstract]
Abstracts
[Back to top]
Editorial:Modifying Cardiovascular
Risk Factors: Novel Cardiovascular Targets for Treatment by
Noninvasive Imaging Techniques
Cardiovascular risk factors, whatever they may be approached
to be studied – and there are a lot of approaches: clinical,
biological, metabolic, epidemiologic, statistic and diagnostic
– lead all to a proven result that is increasing the
incidence of cardiovascular pathology.
The early and careful assessment of cardiovascular risk factors
as well as their influence on functional and metabolic steps
of the heart permit to establish those preventive measures
that may fight myocardial damage.
Cardiovascular risk factors often determine myocardial dysfunction
either structurally or functionally and assessing its degree
and type may be particularly useful.
Diagnostic evidence of physiopathologic features of myocardium
and role of the major cardiovascular risk factors may be,
nowadays, carried out by the use of non-invasive imaging techniques
that, time by time, have met significant progresses in methodology
and applying.
Resting myocardial blood flow, myocardial metabolism, and
cardiovascular function may be correctly interpreted by different
imaging techniques with results that depend on type of applied
methodology, since there are procedures that focus on some
cardiovascular patterns and some on others.
The paper of Landini et al. [1] introduces the prominent
in vivo cardiovascular imaging modalities such as
magnetic resonance imaging, nuclear imaging and ultrasound
from both the physical and molecular imaging perspectives.
A brief introduction to the molecular imaging principles is
also reported. Special emphasis has been given to the imaging
parameters of sensitivity and spatial resolution, and the
trade-off between spatial resolution, image contrast and target
size.
Passacquale et al. [2] underline the typical morphology
of atherosclerotic plaque as well as the role of imaging techniques
to assess it. Detection of early atherogenesis and characterization
of plaque feature are the major end-points of research in
cardiovascular imaging. Different techniques have been proposed
as an instrument for morphological and functional study of
vascular walls. Clinical evidence suggests the usefulness
of atherosclerosis imaging to better define the cardiovascular
risk stratification, the prognosis and the therapeutic approach
to patients.
A very interesting study was conducted by Virdis et al.
[3] on the role, diagnosis and relationship between hypertension
and endothelial dysfunction. A large body of evidence indicates
that patients with essential hypertension, and even more those
with complicated hypertension, display endothelial dysfunction
characterized by impaired NO availability secondary to oxidative
stress production. A dysfunctioning endothelium is an early
marker of the development of atherosclerotic changes and can
also contribute to cardiovascular events. Vascular reactivity
tests represent the most widely used methods in the clinical
assessment of endothelial function. In the last two decades,
many studies have evaluated the endothelium in hypertensive
patients, using different techniques. Several methodologies
were developed to study microcirculation (resistance arteries
and arterioles) and macrocirculation (conduit arteries), both
in coronary and peripheral vascular districts.
No available test to assess endothelial function has sufficient
sensitivity and specificity to be used in clinical practice.
Therefore, the optimal methodology for investigating the multifaceted
aspects of endothelial dysfunction is still under debate.
Only the growing concordant results from different reproducible
and reliable methods exploring endothelial function with different
stimuli will support and strength experimental findings, thus
providing conclusive answers in this area of research.
Leone et al. [4] debate about the main morphological
patterns that characterize myocells as an effect of smoking
exposure. Two morphologic features may be seen as a main result
of the cardiovascular cell damage caused by cigarette smoking:
myocardial cell necrosis and smoke cardiomyopathy that, however,
can lead to cell necrosis in case of chronic prolonged exposure
to tobacco smoke.
Both these pathologic patterns recognize hypoxia as basic
mechanism.
Cardiovascular cell damage may involve either myocardial cell
or coronary artery wall determining a varied but wide spectrum
of alterations.
Necrosis may be well defined as a result of those morphologic
changes which follow cell death in a living tissue or organ
with partial or total loss in their function. All infarcts
of the heart muscle belong to the group of necrotic lesions,
but not all cardiac necroses are necessarily infarcts. Coronarogenic
or non-coronarogenic mechanism following a direct action of
tobacco compounds on myocardial cells may induce myocardial
cell necrosis.
Smoke cardiomyopathy is probably the most typical evidence
of cellular damage induced by cigarette smoking on the myocardium.
The term cardiomyopathy is used to describe all those forms
of degenerative myocardial lesions caused directly by toxics
or metabolic substances and, indirectly, by changes in blood
flow which are able to induce chronic hypoxia. Initially,
smoke cardiomyopathy is not characterized by necrotic phenomena
but, instead, by alterations of those intracellular structures
RNA- related like mitochondria and ribosomes which are primarily
deputed to carry out metabolic and respiratory pathways of
myocardial cells, the function of which strongly depends on
oxygen availability.
Experimental findings documented undoubtedly either the type
of cellular changes or their reproducibility after both acute
or chronic exposure to cigarette smoke.
Kelle et al. [5], in their report, underline that
coronary magnetic resonance imaging is a powerful noninvasive
technique for the combined assessment of coronary artery anatomy
and function. Challenges in coronary artery imaging have been
widely discussed and results obtained in both healthy volunteers
and patients with cardiovascular disease presented. This includes
a short overview of coronary artery vessel lumen and wall
imaging, contrast agents, permeability of the coronary vessel
wall, high-field imaging and imaging of endothelial function.
In the paper of ten Hove and Neubauer [6], the role of magnetic
resonance spectroscopy (MRS) is described. MRS has been used
for several decades to examine the biochemistry of the myocardium
in a non destructive manner. 31P
MRS, in particular, has been used to study heart failure.
31P MRS allows for the detection
of adenosine triphosphate (ATP), the primary energy source
for all energy consuming processes in cardiomyocytes, and
phosphocreatine (PCr). Via the creatine kinase (CK) reaction
PCr forms the primary ATP buffer in the cell and is involved
in transporting the chemical energy from the ATP-producing
mitochondria to the ATP-consuming contractile proteins. MRS
examination of the failing heart has revealed that PCr, and
to a lesser extent, ATP is reduced. These findings have led
to the concept that the heart is energy starved. The additional
application of 1H MRS has
allowed for the detection of total creatine, allowing for
in depth examination of the creatine kinase system. Using
saturation transfer techniques it is also possible to measure
flux through the CK reaction in the intact heart, and the
application of this technique has proven that in the failing
human heart this flux is reduced. In recent years the study
of transgenic animal models by MRS has led to further insights
into the role of energy metabolism in heart failure.
Neglia et al. [7] underline as in Europe the mortality
for cardiovascular disease has progressively increased up
to the last 20 years, when mortality flattened and then tended
to decline. However, while cardiovascular mortality rates,
adjusted for age, continue to decline, the crude mortality
rates remain approximately stable in most western European
countries and even increase in most eastern countries. Hence,
due to the ageing of the population, cardiovascular disease
is still the major cause of death across Europe and a major
cause of morbidity and loss of quality of life. In particular,
with the diffusion of new risk factors (physical inactivity,
diabetes mellitus and obesity), the prevalence of coronary
artery disease (CAD), the most frequent among cardiovascular
diseases, is actually increasing. Accordingly, better prevention
and management of CAD is needed to further reduce early cardiovascular
mortality and morbidity, to improve life expectancy and quality
of life and to reduce sanitary costs. Thus, further achievements
in the fight against cardiovascular disease could be obtained
by developing and testing new strategies for the early detection
and better characterization of CAD. These strategies, based
on non-invasive methods, should allow to identify new reliable
end-points for prevention and treatment. In this regard, Positron
Emission Tomography (PET) may offer a unique opportunity.
The unique capabilities of this advanced radionuclide imaging
technique to quantitate myocardial perfusion can be integrated
with the anatomical details on the coronary circulation provided
by multislice Computed Tomography (CT). The recent diffusion
of PET and PET-CT scanners for use in oncology, allows to
test their use in cardiology. In particular the combined functional
and anatomic information which PET and CT are able to provide
on the heart and coronary vessels may be used as a new non-invasive
strategy for the early detection, functional characterization
and monitoring of CAD.
Authors’ review emphasizes particularly the basis of
non invasive assessment of CAD, the most recent technical
developments and results obtained by PET in cardiovascular
research and clinical cardiology as well as considerations
on potential advantages and pitfalls of PET and PET-CT scanners
for widespread cardiological use.
In conclusion, taken together, the outstanding articles in
this issue provide a current approach to the most used non-invasive
techniques to assess both myocardial function and metabolism
particularly related to major cardiovascular risk factors.
Moreover, describing the characteristic changes that affect
morphologically myocardium following its exposure to smoking
as well as morphological features of atherosclerotic plaque
further contribute to update researchers, physicians and students
on a subject like instrumental cardiovascular assessment yet
widely debated and continously in growth.
References
[1] Landini L, Santarelli MF, Landini L Jr, Positano V. Fundamentals
in cardiovascular imaging technologies. Curr Pharm Des 2008;
14(18): 1745-1752.
[2] Passacquale G, Ferri C, Desideri G. Morphology of atherosclerotic
plaque: its features by imaging study. Curr Pharm Des 2008;
14(18): 1753-1760.
[3] Virdis A, Ghiadoni L, Versari D, Giannarelli C, Salvetti
A, Taddei S. Endothelial function assessment in complicated
hypertension. Curr Pharm Des 2008; 14(18): 1761-1770.
[4] Leone A, Landini L Jr, Biadi O, Balbarini A. Smoking and
cardiovascular system: Cellular features of the damage. Curr
Pharm Des 2008; 14(18): 1771-1777.
[5] Kelle S, Weiss RG, Stubber M. Coronary magnetic resonance
imaging. Curr Pharm Des 2008; 14(18): 1778-1786.
[6] ten Hove M, Neubauer S. The application of NMR Spectroscopy
for the study of heart failure. Curr Pharm Des 2008; 14(18):
1787-1797.
[7] Neglia D, Rimoldi O, Kaufmann PA, Camici PG. Radionuclide
PET and PET/CT in coronary artery disease. Curr Pharm Des
2008; 14(18): 1798-1814.
Luigi Landini
Professor of Biomedical Engineering
University of Pisa
Via Diotisalvi, 2
56126 Pisa, Italy
E-mail: luigi.landini@iet.unipi.it
Aurelio Leone
MD Chief, FRSH
Via Provinciale, 27
19030 Castelnuovo Magra (SP)
Italy
E-mail: reliol@libero.it
[Back to top]
Fundamentals in Cardiovascular Imaging Technologies
L. Landini, M.F. Santarelli, L. Landini Jr. and V. Positano
The aim of this paper is to introduce the prominent in
vivo cardiovascular imaging modalities such as magnetic
resonance imaging, nuclear imaging and ultrasound from both
the physical and molecular imaging perspectives. A brief introduction
to the molecular imaging principles is also reported. Special
emphasis will be given to the imaging parameters of sensitivity
and spatial resolution, and the trade-off between spatial
resolution, image contrast and target size.
[Back to top]
Morphology of Atherosclerotic Plaque: Its Feature
by Imaging Study
G. Passacquale, C. Ferri and G. Desideri
Atherosclerotic plaque plays a crucial role for the development
of ischaemic diseases and, therefore, its early diagnosis
and feature can help to reduce the incidence of cardiovascular
events.
Detection of early atherogenesis and characterization of plaque
feature are the major end-points of research in cardiovascular
imaging. Different techniques have been proposed as instrument
for morphological and functional study of vascular walls.
The purpose of this review is to underline the possibility
of in vivo detecting the different stages of atherogenesis
by using imaging techniques as well as their relationship
with other risk factors in an attempt to assess the meaning
of vascular lesions.
Very promising results seem to emerge by the analysis of the
literature on the subject, although different patterns are
yet to be clarified.
[Back to top]
Endothelial Function Assessment in Complicated Hypertension
A. Virdis, L. Ghiadoni, D. Versari, C. Giannarelli, A.
Salvetti and S. Taddei
A large body of evidence indicates that patients with
essential hypertension, and even more those with complicated
hypertension, are characterized by endothelial dysfunction
characterized by impaired NO availability secondary to oxidative
stress production. A dysfunctioning endothelium is an early
marker of the development of atherosclerotic changes and can
also contribute to cardiovascular events. Vascular reactivity
tests represent the most widely used methods in the clinical
assessment of endothelial function. In the last two decades,
many studies have evaluated the endothelium in hypertensive
patients, using different techniques. Several methodologies
were developed to study microcirculation (resistance arteries
and arterioles) and macrocirculation (conduit arteries), both
in coronary and peripheral vascular districts.
This review will centre on the most relevant available techniques
in the research on endothelial dysfunction in essential hypertension,
their advantages and limitations, focusing on available data
on endothelial dysfunction which characterizes patients with
complicated hy pertension.
No available test to assess endothelial function has sufficient
sensitivity and specificity to be used in clinical practice.
Therefore, the optimal methodology for investigating the multifaceted
aspects of endothelial dysfunction is still under debate.
Only the growing concordant results from different reproducible
and reliable methods exploring endothelial function with different
stimuli will support and strengthen experimental findings,
thus providing conclusive answers in this area of research.
[Back to top]
Smoking and Cardiovascular System: Cellular Features of the
Damage
A. Leone, L. Landini Jr, O. Biadi and A. Balbarini
Two morphological features may be seen as a main result
of the cardiovascular cell damage caused by cigarette smoking:
myocardial cell necrosis and smoke cardiomyopathy that, however,
can lead to cell necrosis in case of chronic prolonged exposure
to tobacco smoke.
Both these pathological patterns recognise hypoxia as the
basic mechanism.
Cardiovascular cell damage may involve either myocardial cell
or coronary artery wall determining a varied but a wide spectrum
of alterations.
Necrosis may be well defined as a result of those morphological
changes which follow cell death in a living tissue or organ
with partial or total loss in their function. All infarcts
of the heart muscle belong to the group of necrotic lesions,
but not all cardiac necroses are necessarily infarcts. Coronarogenic,
or non-coronarogenic mechanism following a direct action of
tobacco compounds on myocardial cells may induce myocardial
cell necrosis.
Smoke cardiomyopathy is probably the most typical evidence
of cellular damage induced by cigarette smoking on the myocardium.
The term cardiomyopathy is used to describe all those forms
of degenerative myocardial lesions caused directly by toxics
or metabolic substances and, indirectly, by changes in blood
flow which are able to induce chronic hypoxia. Initially,
smoke cardiomyopathy is not characterised by necrotic phenomena
but, instead, by alterations of those intracellular structures
RNA- related like mitochondria and ribosomes, which are primarily
deputed to carry out metabolic and respiratory pathways of
myocardial cells, the function of which strongly depends on
oxygen availability.
Experimental findings documented undoubtedly either the type
of cellular changes or their reproducibility after both acute
or chronic exposure to cigarette smoke.
[Back to top]
Coronary Magnetic Resonance Imaging
S. Kelle, R.G. Weiss and M. Stuber
Coronary magnetic resonance imaging is a powerful non-invasive
technique for the combined assessment of coronary artery anatomy
and function. In the present review article, challenges in
coronary artery imaging are discussed and results obtained
in both healthy volunteers and patients with cardiovascular
disease are presented. This includes a short overview of coronary
artery vessel lumen and wall imaging, contrast agents, permeability
of the coronary vessel wall, high-field imaging and imaging
of endothelial function
[Back to top]
The Application of NMR Spectroscopy for the Study of Heart
Failure
M. ten Hove and S. Neubauer
Magnetic resonance spectroscopy (MRS) has been used for
several decades to examine the biochemistry of the myocardium
in a non destructive manner. 31P
MRS, in particular, has been used to study heart failure.
31P MRS allows for the detection
of adenosine triphosphate (ATP), the primary energy source
for all energy consuming processes in cardiomyocytes, and
phosphocreatine (PCr). Via the creatine kinase (CK)
reaction PCr forms the primary ATP buffer in the cell and
is involved in transporting the chemical energy from the ATP-producing
mitochondria to the ATP-consuming contractile proteins. MRS
examination of the failing heart has revealed that PCr, and
to a lesser extent, ATP is reduced. These findings have led
to the concept that the heart is energy starved. The additional
application of 1H MRS has
allowed for the detection of total creatine, allowing for
in depth examination of the creatine kinase system. Using
saturation transfer techniques it is also possible to measure
flux through the CK reaction in the intact heart, and the
application of this technique has proven that in the failing
human heart this flux is reduced. In recent years the study
of transgenic animal models by MRS has led to further insights
into the role of energy metabolism in heart failure.
[Back to top]
Radionuclide PET and PET/CT in Coronary Artery Disease
D. Neglia, O. Rimoldi, P.A. Kaufmann and P.G. Camici
In the present review, the basis of non invasive assessment
of CAD, the most recent technical developments and results
obtained by PET in cardiovascular research and clinical cardiology
are described. PET has provided a wealth of new information
in the field of cardiac pathophysiology and remains the gold
standard for non-invasive measurements of MBF and CFR against
which new techniques should be tested. The possibility to
combine this relevant functional information with the anatomic
details on luminal and arterial wall abnormalities, provided
by multislice CT with or without the use of “hybrid”
scanners, offers new opportunities for comprehensive non-invasive
assessment of CAD and efficacy of new treatments.
[Back to top]
Role of the Autonomic Nervous System and Neuropeptides
in the Development of Obesity in Humans: Targets for Therapy?
J.R. Greenfield and L.V. Campbell
Obesity and type 2 diabetes have reached epidemic proportions
worldwide. These metabolic disorders, particularly obesity,
are characterised by increased basal sympathetic nervous system
(SNS) activity but an impaired sympathetic response to certain
stimuli, such as insulin. Although targeting the SNS may seem
an attractive avenue for the pharmacological prevention and
treatment of obesity and related metabolic disorders, it remains
unknown whether changes in SNS tone are primary and contribute
to the development of these metabolic conditions or whether
they develop secondary to the obese state. This question can
be answered by the study of insulin-resistant individuals
prior to the development of obesity and type 2 diabetes. Using
this model, it has been shown that early insulin resistance
is associated with increased SNS activity in genetically-predisposed
humans. It has been suggested that in insulin-resistant states,
hyperinsulinaemia is the initiating factor that increases
sympathetic neural activity. Over time, adrenoreceptor down-regulation
and/or reduced sensitivity are likely to develop, resulting
in reduced sympathetic responsiveness. In the postprandial
state, this will lead to im-paired diet-induced thermogenesis
and post-prandial fat oxidation, promoting the accumulation
of body fat. More recent evidence demonstrates that stress-induced
SNS overactivity up-regulates Neuropeptide Y, an orexigenic
hormone, and its Y2 receptor, in visceral adipose tissue,
the fat depot most strongly linked to insulin resistance and
type 2 diabetes. There is evidence that SNS overactivity specifically
contributes to the development of abdominal obesity via this
pathway, which could represent a novel target for the prevention
and treatment of abdominal obesity and related metabolic consequences.
[Back to top]
Engineering Silica Particles as Oral Drug Delivery Vehicles
S.P. Rigby, M. Fairhead and C.F. van der Walle
Porous silica particles are emerging as complementary
systems to polyester microspheres for the encapsulation and
controlled delivery of small-organic drugs. Their recent application
in pharmaceutics is strengthened by well-established characterization
and synthetic routes from the chemical engineering sciences.
Silica is an interesting scaffold material for the encapsulation
of organic molecules. It can be formed into hierarchical structures
over a wide range of length scales and interconnectivities.
Encapsulation can therefore be tailored not only to the drug
but the desired release properties. In addition to surfactant-templating
of hierarchical silica structures, polypeptides from marine
organisms may offer biological routes to novel silica materials.
Silica solgels have also been evaluated as delivery vehicles,
particularly with regard to generating hybrid systems with
mesoporous silica or composite xerogels. This review will
first focus on the detailed characterisation of pore size
and structure of mesoporous silica with regards water penetration
and drug diffusion. We then describe the pharmaceutical applications
of silica materials with regard to improving oral bioavailability,
multiparticulate systems for gastroretention or sustained
release, composite xerogels and in vivo biocompatibility.
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