Current Pharmaceutical Design - Volume 14, Issue 18, 2008

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 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.

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.

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 hypertension. 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.

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.

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.

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.

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.

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 insulinresistant 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 impaired 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.

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 sol-gels 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.