Current Pharmaceutical Design - Volume 11, Issue 17, 2005

Stress echocardiography is the combination of 2D echocardiography with a physical, pharmacological or electrical stress. The diagnostic end point for the detection of myocardial ischemia is the induction of a transient worsening in regional function during stress. Stress echocardiography provides similar diagnostic and prognostic accuracy as radionuclide stress perfusion imaging, but at a substantially lower cost, without environmental impact, and with no biohazards for the patient and the physician. Among different stresses of comparable diagnostic and prognostic accuracy, semisupine exercise is the most used, dobutamine the best test for viability, and dipyridamole the safest and simplest pharmacological stress and the most suitable for combined wall motion - coronary flow reserve assessment. The additional clinical benefit of myocardial contrast echocardiography, tissue Doppler imaging and real time 3-D echocardiography has been inconsistent and disappointing, whereas the potential of adding coronary flow reserve evaluation of left anterior descending coronary artery by transthoracic Doppler echocardiography adds another potentially important dimension to stress echocardiography. In spite of its dependence upon operator's training, stress echocardiography is today the best possible imaging choice to achieve the still elusive target of sustainable cardiac imaging in the field of noninvasive diagnosis of coronary artery disease.

Among the available imaging techniques, Magnetic Resonance Imaging (MRI) is gaining an increasing role in the cardiologic setting because its specific properties such as the use of non ionising energies, the natural strong contrast between different tissues, the absence of spatial limitations, the good spatial and temporal resolution, the reduced operator dependency. To further improve the images quality and the histopathologic characterisation of tissues the use of contrast media (molecules containing gadolinium, manganese, iron, dysprosium ions) has been proposed both in the experimental and in the clinical settings. Among these ions gadolinium, which having 7 odd electrons in the external orbit has a strong magnetic momentum, is the most used. Gadolinium by itself is extremely toxic but once it is linked with a chelanting agent such as DTPA (Dietilen-Triamin-Penta-Acetic acid) the resulting complex shows a very low toxicity. The number of Gadolinium based compound is growing together with the use of contrast agents in MRI. These contrast agents are routinely used to perform Magnetic Resonance Angiography (MRA) and to a better definition of several cardiac diseases such as the presence of a intra- or paracardiac mass, the evaluation of myocardial perfusion and the evaluation of viability. Both the latter applications have relevant clinical implications. In fact the assessment of myocardial perfusion is one of the most used approach for detecting inducible myocardial ischemia due to major coronary artery disease or to assess the presence of a microvascular disease. The presence and the extent of viable myocardium is deeply modifying the clinical decision making as this viable tissue can recruit a normal function spontaneously or after revascularisation. Furthermore, the extent of viable myocardium has a strong correlation with negative prognosis. Clinical events are also time related to the detection of viable tissue. These evidences imply that the diagnostic procedure needs the highest level of accuracy. Either in the case of myocardial perfusion and in that of myocardial viability the advantages of MRI with respect to the others techniques are the use of non ionising radiations, the superior spatial resolution, an overall cost/benefit favourable ratio which explains the growing interest among cardiologists toward this new diagnostic tool.

The vascular endothelium has been long viewed as a simply physical separation between blood and tissue [1]. Over the last two decades a consistent bulk of data demonstrated that endothelium is a widely distributed organ, with a variable degree of heterogeneity among and within tissues [2, 3] and deeply involved in vascular physiology and pathophysiology, rather than a cellophane-like membrane that lines the circulatory system [1]. Being positioned at the interface of blood and tissue, the vascular endothelium is able to sense changes in hemodynamic forces and biochemical stimuli and promptly responds to local changes in biological needs by modulating vasomotion, hemostasis, angiogenesis, and vascular growth [1]. The vascular endothelium also modulates the trafficking of circulating blood cells by up-regulating adhesion molecules on cell surface [1, 4, 5]. These cell membrane-associated molecules are critic for leukocyte migration into specific organs under physiologic conditions and accelerate migration towards sites of inflammation [1, 4, 5]. Recently, the multi-step cascade of events that results in the local recruitment of leukocytes to sites of inflammatory challenge, also known as endothelial activation, has been considered as a crucial step in the initiation of atherosclerosis process, as well as in the development of advanced atherosclerosis [6].

Asymmetric dimethylarginine (ADMA) is an endogenously occurring methylarginine that inhibits nitric oxide synthesis. Plasma levels of methylarginines increase in renal failure and certain cardiovascular pathologies, and in patients with end stage renal failure the level of ADMA predicts the risk of cardiovascular events and overall mortality. The object of this review is to describe the mechanisms of ADMA synthesis, metabolism and uptake and to outline techniques for measuring ADMA and the pathological states in which ADMA levels are altered.

Elevated plasma homocyst(e)ine levels have prothrombotic and proatherosclerotic effects. Data from prospective studies indicated that plasma homocyst(e)ine acts as a modest independent predictor of coronary heart disease. At present, no conclusive data are available on the possible interaction between hyperhomocyst(e)inemia and hypertension and the occurrence of cardiovascular events. Recent longitudinal studies in high risk patients indicated that hyperhomocyst(e)inemia is strongly associated with recurrent cardiovascular events. However, this finding is not in line with the few available data from prospective studies, which failed to observe a protective role of homocyst(e)ine-lowering therapy in secondary prevention of cardiovascular events. Future results from ongoing larger trials are expected to provide more definitive answers concerning the need to support the routine use of folic acid in patients with CHD. Since the definitive impact of mild hyperhomocyst(e)inemia on coronary heart disease is still to be established, widespread determination of homocyst(e)ine levels is not needed in a general population at the present time. In contrast, knowledge of homocyst(e)inemia may be important for specific groups of individuals, such as high risk patients, and for those patients in whom traditional risk factors do not appear to account for an increased incidence of cardiovascular events.

There is growing evidence that several biochemical constituents of cigarette smoking play a significant role in the development and progression of heart and blood vessel damage, especially atherosclerotic lesions. Some biochemical markers of tobacco smoke may be determined in blood and urine samples. They are also the main responsible factors of cardiovascular harm. Nicotine and its major metabolite, cotinine, carbon monoxide, and thiocyanate seem to be specific markers. Ischaemic heart disease, cardiac arrhythmias, and endothelial dysfunction are the most common evidence of both active and passive smoking exposure. Dosage of cotinine in urine is of easier determination than that of other metabolites in assessing exposure to smoking, although carboxyhaemoglobin levels seem to be a qualitative, but not quantitative factor to estimate either the degree of cardiovascular damage or the level of exposure. Cigarette smoking is addictive because of nicotine, and it is nicotine withdrawal that causes many side effects of quitting smoking as well as the nicotine itself may exacerbate cardiac lesions. Also haematologic changes are a consequence of cigarette smoking exposure. Increased white blood cells, platelet aggregation and adhesiveness, fibrinogen level, and changes in serum lipids characterise the response to smoking. Anatomical and ultrastructural alterations of the heart and blood vessels are also described as a consequence of negative effects of biochemical markers of cigarette smoking. These alterations are known as “Smoke cardiomyopathy” in experimental pathology.

Lipid markers are well established predictors of vascular disease. The most frequently measured lipid variables are total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and triglycerides. In this review we consider the predictive value of these variables and other more specialised related tests. We also discuss the effect of lipid altering drugs on these markers. The interaction of other vascular risk factors and the lipid effects of non-lipid altering drugs (e.g. blood pressure lowering agents) are also briefly described. Similarly, we discuss the effects of lipid lowering drugs on non-lipid vascular risk factors. Finally, we briefly consider the effect of altering the lipid profile on surrogate markers and events associated with atherosclerosis.

The emerging field of molecular and genomic imaging is providing new opportunities to visualize and quantify the biology of living organisms. To reach such goal all the major imaging modalities concur to this new field, each with its mechanism for generating contrast and with its spatial resolution and specificity. This review deals with a brief introduction to the molecular imaging principles and reports on the state-of-the-art in cardiovascular disease.

The interest for the therapeutic potential of aldosterone antagonists in essential hypertension comes from the recently discovered nonclassical pathways of aldosterone actions, above all the presence of extra-adrenal aldosterone production and the discovery of aldosterone's proinflammatory and profibrotic actions. The review begins with the discussion of experimental studies on animals, demonstrating the role of aldosterone in cardiovascular remodeling and the effects of aldosterone blockade on hypertensive target organ damage. Then recent clinical studies are presented, that confirm in humans the deleterious role of aldosterone, in particular in the development of myocardial hypertrophy, cardiovascular fibrosis and arterial stiffness. After a brief description of the new selective aldosterone antagonist, eplerenone, compared to the well-known non-selective aldosterone antagonist, spironolactone, the results of studies on essential hypertensive patients are discussed, evaluating the efficacy of aldosterone antagonists in lowering blood pressure, but, more important, in protecting against target organ damage.

G-protein-coupled receptors (GPCR) are a major class of membrane proteins belonging to a continuously growing superfamily. These receptors play a critical role in signal transduction, and are among the most important pharmacological drug targets. The first structural model for the GPCR superfamily was the bacterial protein bacteriorhodopsin with its characteristic seven transmembrane (TM) helical architecture. The visual photoreceptor rhodopsin is a better model for GPCR, and the recent elucidation of the crystal structure of bovine rhodopsin has renewed the interest in this receptor as a template for molecular modeling of other GPCR, particularly for the implications in ligand design and drug discovery. In this work different specific structural elements of rhodopsin are reviewed and the role of conserved motifs, like those associated with receptor function, is analyzed. The specific characteristics of the membrane-embedded ligand-binding domain are described. Other aspects, like receptor dimerization or the constitutive activity mechanism, are also outlined. The importance of acquiring knowledge of the active conformation of the receptor by means of both modeling and experimental techniques is also highlighted. In this regard, the model of the activated form of rhodopsin is currently under investigation, and it may provide useful information for pharmaceutical design. Rhodopsin will continue to be a widely used model for GPCR but rhodopsin-based approaches have to be complemented by other theoretical and experimental approaches -while waiting for the crystal structure of other members of the superfamily- if these want to be successfully used for drug discovery.

Most hearing loss results from lesions of the sensory cells and/or neurons of the auditory portion of the inner ear. To date, only the cochlear implantation offers long-term hearing-aid benefit, but still with limited performance and expensive cost. While the underlying causes of deafness are not clear, the death or hair cells and/or neurons and the loss of neuronal contacts are key pathological features. Pinpointing molecular events that control cell death in the cochlea is critical for the development of new strategies to prevent and treat deafness, whether in combination or not with cochlear implant therapy.